_:b504886168 . _:b504886241 . _:b18453261 "The asymmetric modification (H4R3me2a) is mediated by PRMT1, a type I arginine methyltransferase (>>39<<). Although the symmetric dimethylation of arginine by PRMT5 is mainly associated with transcriptional repression, the asymmetric dimethylation mediated by PRMT1 leads to transcriptional activation (39). Because both PRMT5 and SC1 have" . _:b18453247 . _:b18453252 "That this might be a more general role of PRDM family members is suggested by the fact that Blimp1, a critical regulator of primordial germ cell development, has also been shown to down-regulate promitotic genes (>>46<<). Blimp1, like SC1, favors the preservation of the undifferentiated cellular state in primordial germ cells and, also like SC1, exerts its action through recruitment of PRMT5 (25)." . _:b504886278 . _:b504886236 . . . . _:b504886358 . _:b504886334 . . . _:b504886205 . . . _:b504886363 . _:b504886189 . . _:b504886177 . _:b18453223 "Schwann cell factor 1 (SC1) is a protein that was first identified as a binding partner of the p75 neurotrophin receptor (>>21<<). SC1, also known as PRDM4, belongs to the PRDM family of proteins, of which 17 members have been identified in the human genome (22)." . . . _:b18453226 . . . _:b18453264 "Because both PRMT5 and SC1 have been found in association with HDAC1 and HDAC2 (33, >>39<<, 40), it is possible that SC1 might be a common component of the repressive chromatin remodeling complexes during early neural development and that the principal role of SC1 in such complexes might be to provide targeting specificity via" . _:b504886245 . . _:b504886197 . _:b18453220 . _:b18453249 . _:b18453225 . _:b504886335 . . _:b18453217 . _:b18453230 "The different cell types were generated in the appropriate temporal order (>>2<<, 37): Nestin+ precursors were present from the outset, followed by TuJ1+ neurons, GFAP+ astrocytes, and O4+ OLPs at progressively longer culture periods.3 We found that immediately after plating, Nestin+ NSCs could be characterized as" . . _:b504886183 . . _:b504886309 . _:b504886202 . . _:b504886388 . _:b504886371 . _:b504886399 . _:b18453206 . _:b504886162 . _:b18453207 . _:b504886170 . _:b18453208 "Aberrations in the timing of this transition can lead to abnormalities in CNS development (>>5<<, 6)." . . . _:b504886287 . . . . _:b504886255 . _:b18453212 . . _:b504886134 . _:b18453213 . . _:b18453272 . _:b18453214 . _:b504886262 . . _:b18453215 . _:b504886143 . _:b504886151 . _:b18453208 . _:b18453209 . _:b504886397 . _:b18453210 . _:b504886227 . _:b504886182 . _:b18453211 . _:b504886282 . _:b504886296 . _:b18453209 "Aberrations in the timing of this transition can lead to abnormalities in CNS development (5, >>6<<)." . _:b18453220 . _:b18453270 "experimental procedures" . _:b18453265 "Because both PRMT5 and SC1 have been found in association with HDAC1 and HDAC2 (33, 39, >>40<<), it is possible that SC1 might be a common component of the repressive chromatin remodeling complexes during early neural development and that the principal role of SC1 in such complexes might be to provide targeting specificity via its" . _:b18453221 . _:b18453232 . _:b18453222 . _:b18453224 . _:b18453223 . _:b18453216 . _:b504886158 . _:b18453217 . _:b504886294 . _:b504886389 . _:b18453218 . _:b18453219 . _:b504886193 . _:b18453229 "results" . _:b18453228 . _:b504886145 . _:b504886281 . _:b18453229 . _:b18453230 . . . _:b504886184 . _:b18453231 . _:b18453224 . _:b504886274 . _:b18453225 . _:b18453226 . _:b18453227 . _:b504886232 . . _:b18453236 . _:b18453237 . . _:b18453238 . _:b504886345 . _:b18453239 . . . _:b18453232 . _:b18453233 . . _:b18453234 . _:b18453235 . _:b18453273 . . _:b18453244 . . _:b504886175 . . _:b18453245 . _:b504886135 . . _:b18453246 . _:b18453247 . _:b18453242 . _:b504886292 . _:b18453240 . _:b504886357 . _:b18453241 . _:b18453242 . _:b18453250 . _:b18453243 . _:b18453251 . _:b504886186 . _:b18453271 . _:b18453241 "Furthermore, we showed that SC1 in complex with PRMT5 directs H4R3me2s, a modification that is prevalent in the developing neuroepithelium during the expansion phase of cortical development (>>35<<). In addition, we demonstrated that the SC1-PRMT5 complex modulates the levels of expression of promitotic genes that regulate the G2/M transition and mitotic progression." . . _:b504886319 . _:b504886277 "2"^^ . . _:b504886157 . _:b504886359 . _:b504886276 "2"^^ . . _:b504886279 "2"^^ . _:b504886313 . _:b504886278 "2"^^ . _:b18453263 . _:b504886273 "2"^^ . _:b504886329 . _:b504886272 "2"^^ . . _:b504886275 "2"^^ . _:b504886291 . _:b504886274 "2"^^ . _:b18453215 "In addition to cell lineage-specific transcription factors, cell cycle parameters such as the length of specific cell cycle stages play an important role in controlling NSC proliferation and differentiation (>>5<<, 6, 15\u201317), and these parameters change during cortical development (18)." . _:b504886406 . _:b504886285 "2"^^ . _:b504886404 . _:b504886284 "2"^^ . _:b18453247 . _:b504886322 . _:b504886287 "2"^^ . _:b504886286 "2"^^ . _:b18453217 . _:b504886281 "2"^^ . _:b504886280 "2"^^ . _:b504886283 "2"^^ . _:b504886282 "2"^^ . _:b504886315 . _:b504886375 . _:b504886293 "2"^^ . _:b504886247 . _:b504886292 "2"^^ . _:b18453226 . _:b504886295 "2"^^ . . _:b504886294 "2"^^ . . _:b504886289 "2"^^ . _:b504886235 . _:b504886288 "2"^^ . . _:b504886291 "2"^^ . _:b504886263 . _:b504886290 "2"^^ . . _:b18453211 . . _:b504886269 . _:b504886301 "2"^^ . _:b504886300 "2"^^ . _:b504886185 . . _:b504886394 . _:b504886303 "2"^^ . _:b504886248 . _:b504886302 "2"^^ . _:b18453217 "In addition to cell lineage-specific transcription factors, cell cycle parameters such as the length of specific cell cycle stages play an important role in controlling NSC proliferation and differentiation (5, 6, >>15<<\u201317), and these parameters change during cortical development (18)." . _:b18453233 "Purified histones from calf thymus were incubated with immunoprecipitated mycSC1 and subjected to an in vitro radioactive HMTase assay (>>38<<). We detected methylated histones, the preferred substrate being histone H4 (Fig. 3A). As a positive control, we immunoprecipitated Myc-Su(var)3\u20139, an H3K9 HMTase, and showed that this preferentially methylated histone H3 (Fig. 3A). As" . _:b504886297 "2"^^ . . _:b504886296 "2"^^ . _:b504886299 "2"^^ . _:b504886244 . . _:b504886298 "2"^^ . _:b504886309 "2"^^ . _:b504886139 . _:b504886230 . _:b504886133 . _:b504886308 "2"^^ . _:b504886132 . . _:b504886311 "2"^^ . . _:b504886135 . _:b504886310 "2"^^ . _:b504886134 . _:b504886305 "2"^^ . _:b504886304 "2"^^ . . _:b18453262 "Although the symmetric dimethylation of arginine by PRMT5 is mainly associated with transcriptional repression, the asymmetric dimethylation mediated by PRMT1 leads to transcriptional activation (>>39<<). Because both PRMT5 and SC1 have been found in association with HDAC1 and HDAC2 (33, 39, 40), it is possible that SC1 might be a common component of the repressive chromatin remodeling complexes during early neural development and that" . _:b504886307 "2"^^ . _:b504886131 . _:b504886306 "2"^^ . . _:b504886368 . _:b504886130 . _:b504886317 "2"^^ . "PMC0" . . _:b504886141 . _:b504886316 "2"^^ . _:b504886285 . _:b504886140 . _:b504886319 "2"^^ . _:b18453234 "Therefore, we asked whether PRMT5, a type II PRMT that is known to catalyze H4R3me2s (>>39<<, 40), might interact with SC1 protein." . . _:b504886376 . _:b504886143 . _:b504886318 "2"^^ . _:b504886142 . . _:b504886313 "2"^^ . _:b504886351 . . _:b504886137 . _:b504886223 . _:b504886312 "2"^^ . _:b504886338 . _:b504886136 . _:b504886315 "2"^^ . _:b504886139 . . _:b504886314 "2"^^ . . _:b504886138 . . _:b504886325 "2"^^ . _:b504886149 . _:b504886324 "2"^^ . _:b504886153 . _:b504886384 . _:b504886148 . _:b504886327 "2"^^ . . _:b504886151 . _:b504886326 "2"^^ . _:b504886150 . _:b504886321 "2"^^ . _:b504886145 . _:b504886320 "2"^^ . . _:b504886374 . _:b504886314 . _:b504886144 . . _:b504886323 "2"^^ . _:b504886392 . _:b504886147 . _:b504886322 "2"^^ . _:b504886146 . _:b504886333 "2"^^ . _:b504886157 . _:b504886332 "2"^^ . . _:b504886156 . _:b504886335 "2"^^ . _:b504886148 . _:b504886159 . _:b504886334 "2"^^ . . _:b504886158 . _:b504886329 "2"^^ . _:b504886153 . _:b504886328 "2"^^ . _:b504886152 . _:b504886331 "2"^^ . . _:b504886155 . _:b504886330 "2"^^ . _:b504886154 . _:b504886341 "2"^^ . _:b504886348 . _:b504886165 . _:b504886340 "2"^^ . _:b504886164 . . . . _:b504886343 "2"^^ . _:b504886167 . _:b504886342 "2"^^ . _:b18453271 "Primary neural stem cells were isolated from mouse E10.5 cerebral cortices according to published procedures (>>36<<). Briefly, the cortices were harvested in EBSS (Invitrogen), and the meninges were removed." . _:b504886166 . . . _:b504886337 "2"^^ . _:b504886161 . _:b504886336 "2"^^ . _:b18453269 "Given that SC1 is a p75 neurotrophin receptor-interacting protein (>>21<<), it will be important to determine whether neurotrophins or other signaling molecules can trigger modifications of SC1 that regulate its ability to recruit PRMT5 and thereby transmit extracellular information to the nuclear interior." . _:b504886160 . _:b504886339 "2"^^ . _:b18453256 "Its role in preserving the less differentiated cellular state has been demonstrated in PGCs, erythrocyte progenitors, and ES cells (25, 41, >>46<<, 47). We now provide evidence that PRMT5 is also expressed in developing NSCs during their stem-like proliferative stage of development. Together, these observations suggest a fundamental role for PRMT5 and its cognate modifications," . _:b18453269 . _:b504886163 . _:b504886338 "2"^^ . _:b504886162 . _:b504886349 "2"^^ . . _:b504886173 . _:b504886348 "2"^^ . . _:b504886172 . _:b504886351 "2"^^ . _:b504886175 . _:b504886350 "2"^^ . . _:b18453224 "SC1, also known as PRDM4, belongs to the PRDM family of proteins, of which 17 members have been identified in the human genome (>>22<<). All of the PRDM family members are characterized by the presence of a positive regulatory (PR) domain and multiple zinc finger domains. The PR domains are similar to but distinct from the SET domains found in many histone lysine" . _:b504886174 . _:b504886345 "2"^^ . . . _:b504886169 . _:b504886344 "2"^^ . _:b504886164 . _:b504886168 . _:b504886347 "2"^^ . _:b18453260 . _:b18453253 . _:b504886171 . _:b504886346 "2"^^ . _:b18453254 . . _:b504886170 . _:b504886357 "2"^^ . . . _:b18453227 "Our previous work identified SC1/PRDM4 as an HDAC-associated transcriptional repressor that modulates cell cycle progression (>>33<<). SC1 is highly expressed in the developing mouse cerebral cortex (34), so we set out to understand its role in the development of cortical NSCs as they switch from proliferative to neuron-generating divisions. We report that SC1 recruits" . _:b504886181 . _:b504886356 "2"^^ . . _:b504886180 . _:b504886359 "2"^^ . _:b504886183 . _:b504886358 "2"^^ . . _:b504886182 . _:b504886353 "2"^^ . . _:b504886177 . . _:b504886352 "2"^^ . _:b504886267 . _:b504886176 . _:b504886355 "2"^^ . _:b504886166 . _:b504886179 . _:b504886354 "2"^^ . _:b504886178 . _:b504886365 "2"^^ . _:b504886189 . _:b504886364 "2"^^ . _:b504886188 . _:b18453207 "of the brain and spinal cord first proliferate symmetrically to increase NSC numbers and expand the ventricular zone, and then they switch to an asymmetric mode of division to generate postmitotic neurons while maintaining the NSC pool (>>1<<\u20134). After neurogenesis is complete, the NSCs switch to production of glial cells (astrocytes and oligodendrocytes)." . _:b504886367 "2"^^ . _:b504886203 . _:b504886191 . _:b504886366 "2"^^ . . _:b504886190 . _:b18453244 "3 Similarly, another PRDM family member, Blimp1/PRDM1, has been reported to undergo temporally dynamic expression during development of primordial germ cells and various other tissues (44, >>45<<) and has also been shown to recruit PRMT5 during primordial germ cell development (25)." . _:b504886361 "2"^^ . _:b504886185 . _:b18453267 "Moreover, it was previously shown that in PC12 cells, which can respond to NGF by differentiating into sympathetic-like neurons, application of NGF increases asymmetric arginine dimethylation of proteins mediated by PRMT1 (>>49<<, 50). Taken together, these observations suggest that NSC division and neurogenesis is at least partly regulated by the sequential activation of PRMT5 and PRMT1; high levels of SC1-PRMT5 protein complex during the proliferative stage of" . _:b504886360 "2"^^ . . _:b504886184 . _:b504886363 "2"^^ . _:b504886187 . _:b504886362 "2"^^ . _:b504886186 . _:b504886373 "2"^^ . _:b504886197 . _:b504886372 "2"^^ . _:b18453252 . . _:b504886196 . _:b504886375 "2"^^ . _:b18453253 . . _:b504886199 . _:b504886374 "2"^^ . _:b18453254 . _:b18453241 . . _:b18453226 . _:b504886198 . _:b504886369 "2"^^ . _:b18453255 . _:b504886326 . _:b504886193 . _:b18453230 . . _:b504886368 "2"^^ . _:b18453248 . _:b504886192 . _:b504886371 "2"^^ . _:b18453249 . . _:b504886195 . _:b504886370 "2"^^ . _:b18453250 . _:b504886398 . _:b504886290 . _:b504886194 . . _:b504886381 "2"^^ . _:b18453251 . _:b504886152 . _:b504886205 . _:b504886380 "2"^^ . _:b18453260 . . _:b504886204 . _:b504886146 . _:b18453261 . _:b504886383 "2"^^ . _:b504886317 . _:b504886207 . _:b18453236 "SC1 and PRMT5 were found in the nucleus and cytoplasm of neuroepithelial cells, suggesting that part of their mode of action might be through methylation of a cytoplasmic pool of newly synthesized histones (>>41<<). To investigate whether we can detect a complex between the endogenous SC1 and PRMT5 in the developing cortex, we performed an immunoprecipitation using mouse E10.5 cortices as the source of endogenous PRMT5 and SC1 proteins. PRMT5 was" . _:b504886382 "2"^^ . _:b18453262 . _:b504886206 . _:b504886377 "2"^^ . _:b18453263 . _:b18453248 . . _:b18453235 . _:b504886201 . _:b504886376 "2"^^ . _:b18453256 . _:b504886200 . . _:b18453257 . _:b18453228 . _:b504886379 "2"^^ . _:b504886203 . _:b504886378 "2"^^ . _:b18453258 . . _:b504886202 . _:b504886389 "2"^^ . _:b18453259 . _:b504886213 . _:b18453240 _:b18453252 . _:b18453268 . _:b504886388 "2"^^ . _:b18453240 _:b18453253 . _:b18453240 _:b18453254 . _:b18453240 _:b18453255 . _:b504886212 . _:b18453240 _:b18453248 . _:b18453269 . _:b504886391 "2"^^ . _:b18453240 _:b18453249 . . _:b18453240 _:b18453250 . _:b18453240 _:b18453251 . _:b504886215 . _:b18453240 _:b18453260 . _:b504886390 "2"^^ . _:b18453270 . _:b18453240 _:b18453261 . _:b18453240 _:b18453262 . . _:b18453240 _:b18453263 . _:b504886214 . _:b18453240 _:b18453256 . _:b18453271 . _:b504886385 "2"^^ . _:b18453240 _:b18453257 . _:b18453219 "Lineage-specific transcription factors (>>5<<) can fine-tune the expression of cell cycle genes and in this way influence the cell fates and division modes of NSCs and consequently their decision either to proliferate or differentiate (16, 19, 20)." . _:b18453240 _:b18453258 . _:b18453240 _:b18453259 . _:b504886209 . _:b18453240 _:b18453268 . _:b18453264 . _:b504886384 "2"^^ . _:b18453240 _:b18453269 . _:b504886131 . _:b504886208 . . _:b18453240 _:b18453264 . _:b18453265 . _:b504886387 "2"^^ . _:b18453240 _:b18453265 . _:b18453245 . _:b18453240 _:b18453266 . _:b504886379 . _:b18453240 _:b18453267 . _:b18453212 . _:b504886211 . _:b504886386 "2"^^ . _:b18453266 . _:b504886210 . _:b504886397 "2"^^ . _:b18453267 . _:b504886221 . . _:b504886396 "2"^^ . . _:b504886220 . _:b504886399 "2"^^ . _:b504886223 . _:b504886398 "2"^^ . _:b504886222 . _:b18453231 . _:b18453207 . _:b504886393 "2"^^ . . _:b504886217 . _:b504886392 "2"^^ . _:b18453272 . _:b504886216 . _:b504886395 "2"^^ . _:b18453273 . _:b18453250 "High levels and activity of these classical regulators of mitosis were found to be necessary for asymmetric division of the neuroblasts during development (19, >>20<<). In this respect, our finding of diminished expression of both SC1 and to a lesser extent PRMT5 in the developing cortex at E12 and E13.5, when the NSCs switch from symmetric proliferative divisions to asymmetric neuron-generating ones," . . _:b504886219 . _:b504886394 "2"^^ . _:b504886218 . _:b504886352 . _:b504886405 "2"^^ . _:b504886229 . _:b18453238 "P19 cells were chosen because they can be differentiated into neural lineages under defined culture conditions (>>42<<) and are easily transfected to high efficiency." . _:b504886404 "2"^^ . _:b504886228 . . _:b504886231 . _:b504886406 "2"^^ . . . _:b504886230 . _:b504886401 "2"^^ . _:b504886225 . _:b504886400 "2"^^ . _:b504886224 . _:b504886403 "2"^^ . _:b504886227 . _:b504886402 "2"^^ . _:b18453249 "High levels and activity of these classical regulators of mitosis were found to be necessary for asymmetric division of the neuroblasts during development (>>19<<, 20). In this respect, our finding of diminished expression of both SC1 and to a lesser extent PRMT5 in the developing cortex at E12 and E13.5, when the NSCs switch from symmetric proliferative divisions to asymmetric neuron-generating" . _:b18453226 . _:b504886270 . _:b504886226 . _:b504886237 . _:b504886236 . _:b504886308 . _:b504886239 . . . . _:b504886238 . _:b504886233 . "10.1074%2Fjbc.M112.392746" . _:b504886232 . _:b504886235 . _:b18453214 . _:b18453234 . _:b504886234 . _:b18453210 "In the developing cerebral cortex NSCs generate a series of neuronal subtypes that populate different cortical layers in sequence and then switch to glial cell production (>>7<<, 8). This program of neurogenesis can be recapitulated by individual mouse cortical NSCs isolated at embryonic day 10 (E10) and cultured at low density in vitro (2, 3)." . . _:b504886245 . _:b18453216 "In addition to cell lineage-specific transcription factors, cell cycle parameters such as the length of specific cell cycle stages play an important role in controlling NSC proliferation and differentiation (5, >>6<<, 15\u201317), and these parameters change during cortical development (18)." . _:b504886244 . . _:b504886325 . _:b504886247 . _:b504886211 . . _:b504886320 . _:b504886155 . _:b504886246 . . _:b504886241 . . _:b504886240 . _:b504886196 . _:b504886243 . _:b504886377 . . _:b504886242 . _:b504886253 . . _:b504886252 . . _:b18453226 "modifiers in their own right or else they recruit third party chromatin modifiers\u2014e.g., histone deacetylases (HDACs), histone lysine MTases, or histone arginine MTases\u2014to regulate cell type-specific gene expression in various tissues (>>24<<\u201333). Our previous work identified SC1/PRDM4 as an HDAC-associated transcriptional repressor that modulates cell cycle progression (33)." . _:b504886255 . _:b504886257 . _:b504886254 . . _:b504886249 . _:b504886187 . _:b18453213 "This program of neurogenesis can be recapitulated by individual mouse cortical NSCs isolated at embryonic day 10 (E10) and cultured at low density in vitro (2, >>3<<). This suggests that the temporal program of NSC division and cell fate specification is cell intrinsic, but the molecular nature of the program is not known. The transitions in NSC fate are likely to be governed by cell lineage-specific" . _:b504886248 . . . _:b504886312 . _:b504886251 . _:b504886250 . . _:b18453213 . _:b504886261 . _:b504886260 . _:b504886393 . _:b504886263 . _:b504886228 . _:b18453262 . _:b504886207 . _:b504886141 . _:b504886301 . . _:b18453226 . _:b504886262 . _:b504886257 . _:b504886138 . _:b18453236 . _:b504886256 . _:b504886231 . _:b18453261 . . _:b18453256 . _:b18453214 . _:b504886305 . _:b504886259 . . _:b504886258 . _:b504886367 . _:b504886269 . . . _:b18453254 "Its role in preserving the less differentiated cellular state has been demonstrated in PGCs, erythrocyte progenitors, and ES cells (>>25<<, 41, 46, 47)." . _:b504886266 . _:b504886268 . . _:b18453207 . _:b504886271 . . _:b504886270 . _:b504886265 . _:b504886403 . _:b504886264 . _:b504886137 . _:b18453226 . _:b504886267 . _:b504886133 . _:b504886266 . . . _:b504886386 . _:b18453264 . _:b504886361 . _:b18453252 . _:b504886300 . . _:b504886156 . . _:b504886237 . _:b18453214 . . _:b504886169 . _:b504886261 . . _:b504886190 . . . _:b18453251 "High levels of SC1-PRMT5 complex found in the preneurogenic cortex at E10.5 may keep the expression of promitotic genes cycB and Bub1b low and might therefore favor symmetric divisions (>>20<<), indirectly inhibiting neuronal differentiation, a possibility that should be tested in future investigations." . . . _:b504886321 . _:b504886209 . _:b504886174 . . _:b504886293 . _:b18453245 "Blimp1/PRDM1, has been reported to undergo temporally dynamic expression during development of primordial germ cells and various other tissues (44, 45) and has also been shown to recruit PRMT5 during primordial germ cell development (>>25<<). Importantly, various levels of Blimp appear to be necessary to direct differentiation of different tissues, reflecting precise dose dependence of different cell types on Blimp1 requirement (45)." . _:b18453219 . . _:b18453246 "Importantly, various levels of Blimp appear to be necessary to direct differentiation of different tissues, reflecting precise dose dependence of different cell types on Blimp1 requirement (>>45<<). These observations highlight the general principle of utilizing the same transcriptional regulators during development in various tissues in a graded manner to specify different cell fates, possibly through recruitment of different" . . _:b18453206 _:b18453228 . . _:b18453206 _:b18453224 . _:b18453206 _:b18453225 . _:b18453206 _:b18453226 . . _:b18453206 _:b18453227 . _:b18453206 _:b18453220 . _:b18453206 _:b18453221 . _:b18453206 _:b18453222 . . _:b18453206 _:b18453223 . _:b18453206 _:b18453216 . _:b18453206 _:b18453217 . . _:b18453248 "of these cells to extracellular signals. Moreover, the observation that both SC1 and PRMT5 are found at high levels in the developing OLPs where PRMT5 has been shown to be necessary for OLP differentiation (this paper and Ref. >>17<<) further underscores the principle of utilizing the same transcription factors in a graded manned throughout development to direct different developmental outcomes." . _:b18453206 _:b18453218 . _:b18453206 _:b18453219 . _:b18453206 _:b18453212 . _:b18453206 _:b18453213 . _:b504886336 . _:b18453206 _:b18453214 . _:b18453206 _:b18453215 . _:b18453206 _:b18453208 . . _:b18453206 _:b18453209 . _:b18453206 _:b18453210 . _:b18453206 _:b18453211 . _:b18453206 _:b18453207 . . _:b504886217 . . . . _:b18453259 "Intriguingly, high PRMT5 activity was sustained by proliferation-inducing growth factors that favor symmetric divisions, whereas differentiation-inducing growth factors dampened PRMT5 activity, leading to cellular differentiation (>>48<<)." . _:b18453240 "discussion" . . _:b504886226 . _:b18453257 "Its role in preserving the less differentiated cellular state has been demonstrated in PGCs, erythrocyte progenitors, and ES cells (25, 41, 46, >>47<<). We now provide evidence that PRMT5 is also expressed in developing NSCs during their stem-like proliferative stage of development. Together, these observations suggest a fundamental role for PRMT5 and its cognate modifications, H4R3me2s" . _:b504886369 . _:b18453243 . _:b504886401 . _:b504886354 . . _:b504886387 . _:b504886246 . _:b18453223 . _:b18453229 _:b18453232 . _:b504886349 . . _:b18453229 _:b18453233 . _:b18453229 _:b18453234 . . _:b18453229 _:b18453235 . _:b18453229 _:b18453236 . _:b18453229 _:b18453237 . _:b18453229 _:b18453238 . _:b18453229 _:b18453239 . . _:b504886171 . . _:b504886253 . . _:b18453226 . _:b504886201 . . _:b18453226 . _:b504886142 . . _:b18453229 _:b18453230 . _:b504886215 . _:b18453229 _:b18453231 . . _:b504886333 . _:b18453244 . . _:b504886173 . _:b18453246 . . . _:b504886140 . _:b504886141 . _:b504886142 . _:b504886143 . _:b504886240 . _:b504886136 . _:b504886137 . _:b18453220 "Lineage-specific transcription factors (5) can fine-tune the expression of cell cycle genes and in this way influence the cell fates and division modes of NSCs and consequently their decision either to proliferate or differentiate (>>16<<, 19, 20)." . _:b504886138 . _:b18453266 "is also noteworthy in this respect that previous work has identified a protein, Tis21/Btg2, a known stimulator of PRMT1 activity, as a marker of NSCs that are undergoing their final mitosis on their way to becoming postmitotic neurons (>>18<<). Moreover, it was previously shown that in PC12 cells, which can respond to NGF by differentiating into sympathetic-like neurons, application of NGF increases asymmetric arginine dimethylation of proteins mediated by PRMT1 (49, 50)." . _:b504886139 . . _:b504886132 . _:b504886133 . _:b504886134 . _:b504886135 . _:b504886318 . _:b504886130 . _:b504886131 . _:b18453240 _:b18453244 . _:b18453240 _:b18453245 . _:b18453240 _:b18453246 . _:b18453240 _:b18453247 . _:b18453240 _:b18453241 . . _:b18453240 _:b18453242 . _:b18453240 _:b18453243 . . . . . _:b504886347 . . _:b504886234 . _:b18453212 "This program of neurogenesis can be recapitulated by individual mouse cortical NSCs isolated at embryonic day 10 (E10) and cultured at low density in vitro (>>2<<, 3). This suggests that the temporal program of NSC division and cell fate specification is cell intrinsic, but the molecular nature of the program is not known. The transitions in NSC fate are likely to be governed by cell" . _:b18453215 . _:b504886250 . . _:b18453208 . . . . _:b18453266 . _:b504886280 . _:b504886136 . . _:b18453270 . _:b504886355 . . _:b504886258 . _:b504886402 . _:b504886373 . . _:b504886350 . . . _:b504886132 . . _:b18453239 . _:b18453226 . _:b18453206 "introduction" . _:b504886302 . _:b504886339 . _:b504886134 "7"^^ . _:b504886135 "7"^^ . _:b18453265 . _:b504886268 . _:b504886269 . . _:b504886270 . _:b504886271 . _:b504886132 "8"^^ . _:b504886130 . _:b504886264 . _:b504886265 . _:b504886266 . _:b504886267 . _:b504886133 "8"^^ . _:b504886395 . _:b504886260 . _:b504886261 . . _:b504886262 . _:b504886263 . _:b504886256 . _:b504886130 "9"^^ . _:b504886257 . _:b504886258 . . _:b504886259 . _:b504886131 "8"^^ . _:b504886252 . _:b504886253 . _:b504886254 . _:b504886255 . _:b504886248 . _:b504886249 . _:b504886250 . _:b504886251 . _:b504886244 . _:b504886245 . _:b504886246 . _:b504886214 . _:b504886247 . _:b504886240 . _:b504886141 "5"^^ . _:b504886241 . _:b504886242 . _:b504886243 . _:b504886236 . _:b504886140 "5"^^ . _:b504886237 . _:b504886238 . _:b504886239 . _:b504886232 . _:b504886396 . _:b504886143 "5"^^ . _:b504886233 . _:b504886234 . _:b504886235 . _:b504886228 . _:b18453222 . _:b504886142 "5"^^ . _:b504886229 . . _:b504886230 . _:b504886138 "6"^^ . _:b504886231 . . _:b504886224 . _:b504886225 . _:b504886226 . _:b504886227 . _:b18453228 "a type II arginine MTase, PRMT5, that catalyzes histone H4R3 symmetric dimethylation (H4R3me2s), a modification that we recently showed to be present in undifferentiated NSCs in the murine cortex prior to the onset of neurogenesis (>>35<<). We now show that both SC1 and PRMT5 are highly expressed in the preneurogenic cortex and provide evidence that the interaction between SC1 and PRMT5 regulates the proliferative capacity of cultured cortical NSCs." . _:b18453211 "In the developing cerebral cortex NSCs generate a series of neuronal subtypes that populate different cortical layers in sequence and then switch to glial cell production (7, >>8<<). This program of neurogenesis can be recapitulated by individual mouse cortical NSCs isolated at embryonic day 10 (E10) and cultured at low density in vitro (2, 3)." . _:b504886220 . _:b504886332 . _:b504886221 . _:b504886136 "6"^^ . _:b504886222 . . . _:b504886277 . _:b504886265 . _:b504886223 . _:b504886340 . _:b504886216 . _:b504886139 "5"^^ . . _:b504886217 . _:b504886137 "6"^^ . _:b504886218 . _:b504886276 . _:b504886219 . _:b504886212 . _:b18453268 . _:b504886213 . _:b504886214 . _:b504886279 . _:b504886215 . _:b504886149 "4"^^ . _:b504886208 . _:b504886209 . _:b504886210 . _:b504886278 . _:b504886211 . _:b504886204 . _:b504886148 "5"^^ . _:b504886205 . _:b504886206 . _:b504886273 . _:b504886207 . _:b504886151 "4"^^ . _:b504886200 . _:b504886256 . _:b504886201 . _:b504886202 . _:b504886272 . _:b504886203 . . _:b504886150 "4"^^ . . _:b504886196 . _:b504886197 . _:b504886198 . _:b504886275 . _:b504886199 . _:b504886192 . _:b504886400 . _:b504886145 "5"^^ . _:b504886193 . _:b504886194 . _:b504886274 . . _:b504886195 . _:b504886188 . _:b18453229 . _:b504886144 "5"^^ . _:b504886189 . _:b504886190 . _:b504886285 . _:b504886191 . _:b504886184 . _:b504886147 "5"^^ . _:b504886185 . _:b504886186 . . _:b504886284 . _:b504886187 . _:b504886180 . _:b504886146 "5"^^ . _:b504886181 . _:b504886182 . _:b504886287 . _:b504886183 . _:b504886276 . _:b504886157 "4"^^ . _:b504886176 . _:b504886177 . . _:b504886178 . _:b504886286 . _:b504886378 . _:b504886179 . _:b504886156 "4"^^ . _:b504886172 . _:b504886173 . _:b504886174 . _:b504886281 . _:b18453240 . _:b504886175 . _:b504886159 "4"^^ . _:b504886168 . _:b504886169 . . _:b504886170 . _:b504886280 . _:b504886171 . _:b504886158 "4"^^ . _:b504886164 . _:b504886165 . _:b504886166 . . _:b504886283 . _:b504886167 . _:b504886153 "4"^^ . _:b504886220 . _:b504886160 . _:b504886161 . _:b504886162 . _:b504886282 . _:b504886163 . _:b504886152 "4"^^ . _:b504886156 . _:b504886157 . _:b504886158 . _:b504886293 . _:b504886159 . . _:b504886155 "4"^^ . _:b504886152 . _:b504886153 . _:b504886154 . _:b18453209 . _:b504886292 . _:b504886155 . _:b504886154 "4"^^ . _:b504886148 . . _:b504886149 . _:b504886150 . . _:b504886295 . _:b504886151 . . _:b504886165 "4"^^ . _:b504886144 . _:b504886145 . _:b504886146 . _:b504886294 . _:b504886147 . _:b504886164 "4"^^ . . _:b504886289 . _:b504886167 "4"^^ . _:b504886288 . _:b504886166 "4"^^ . _:b18453206 . _:b504886291 . _:b504886161 "4"^^ . _:b504886290 . _:b504886160 "4"^^ . _:b18453216 . _:b504886301 . _:b504886163 "4"^^ . . . _:b504886300 . _:b504886162 "4"^^ . _:b18453272 "The cells were cultured in DMEM supplemented with 10 ng/ml basic FGF (PeproTech), 0.25% FCS, B27 supplement, sodium pyruvate, and glutamine (all from Invitrogen) (>>2<<). The cultures were routinely immunolabeled to monitor their ability to generate neurons, astrocytes, and oligodendrocytes." . . _:b504886219 . _:b504886303 . . . _:b504886210 . _:b504886173 "4"^^ . _:b504886295 . _:b504886259 . _:b18453255 "Its role in preserving the less differentiated cellular state has been demonstrated in PGCs, erythrocyte progenitors, and ES cells (25, >>41<<, 46, 47). We now provide evidence that PRMT5 is also expressed in developing NSCs during their stem-like proliferative stage of development. Together, these observations suggest a fundamental role for PRMT5 and its cognate modifications," . _:b504886302 . _:b504886172 "4"^^ . _:b504886271 . . _:b504886279 . . _:b504886179 . _:b504886175 "3"^^ . _:b504886330 . _:b504886297 . _:b504886174 "3"^^ . . _:b504886296 . . _:b504886299 . _:b504886169 "4"^^ . . _:b504886298 . _:b504886168 "4"^^ . . _:b18453243 "3 Similarly, another PRDM family member, Blimp1/PRDM1, has been reported to undergo temporally dynamic expression during development of primordial germ cells and various other tissues (>>44<<, 45) and has also been shown to recruit PRMT5 during primordial germ cell development (25)." . _:b504886309 . _:b504886171 "4"^^ . . _:b504886308 . _:b504886170 "4"^^ . . . _:b504886180 . _:b504886311 . _:b504886181 "3"^^ . . _:b504886264 . . _:b504886180 "3"^^ . . _:b504886310 . _:b504886183 "3"^^ . . _:b504886305 . _:b504886327 . . _:b504886304 . _:b504886182 "3"^^ . . . . . _:b504886177 "3"^^ . _:b504886307 . _:b504886176 "3"^^ . _:b504886306 . . _:b504886317 . _:b504886179 "3"^^ . _:b504886178 "3"^^ . _:b504886316 . _:b18453233 . _:b504886297 . _:b504886268 . . _:b504886189 "3"^^ . _:b504886319 . _:b504886304 . . _:b504886188 "3"^^ . _:b504886318 . _:b504886286 . _:b504886191 "3"^^ . _:b504886313 . . _:b504886312 . _:b504886190 "3"^^ . _:b504886185 "3"^^ . _:b18453239 "It was previously reported that a high level and activity of the cell cycle regulator cdc2, in association with cycB, is necessary for the asymmetric partitioning of cell fate determinants in neuroblasts of Drosophila melanogaster (>>20<<). These observations suggest that the levels and activity of promitotic genes might be involved in influencing the mode of cell division adopted by the NSCs." . _:b504886315 . . _:b18453214 . _:b504886184 "3"^^ . _:b504886314 . . . _:b504886187 "3"^^ . _:b18453222 "transcription factors (5) can fine-tune the expression of cell cycle genes and in this way influence the cell fates and division modes of NSCs and consequently their decision either to proliferate or differentiate (16, 19, >>20<<)." . _:b504886325 . _:b504886186 "3"^^ . _:b504886324 . _:b504886197 "3"^^ . _:b504886327 . . _:b504886196 "3"^^ . _:b504886326 . _:b504886323 . _:b504886344 . _:b504886199 "3"^^ . _:b504886321 . _:b504886198 "3"^^ . _:b504886320 . _:b504886193 "3"^^ . _:b504886323 . _:b504886192 "3"^^ . _:b504886322 . _:b18453221 . . _:b504886195 "3"^^ . _:b504886333 . _:b504886194 "3"^^ . _:b504886332 . _:b504886205 "3"^^ . _:b504886335 . _:b504886204 "3"^^ . _:b504886334 . . _:b504886207 "3"^^ . _:b504886329 . . _:b504886206 "3"^^ . _:b504886328 . . _:b504886216 . . _:b504886178 . _:b504886201 "3"^^ . _:b504886331 . _:b504886200 "3"^^ . _:b504886341 . _:b504886330 . _:b504886203 "3"^^ . _:b504886341 . _:b504886202 "3"^^ . _:b504886340 . _:b18453247 . _:b504886213 "3"^^ . _:b504886343 . _:b504886365 . _:b18453207 . _:b18453270 _:b18453272 . . _:b18453270 _:b18453273 . . _:b504886212 "3"^^ . _:b504886342 . . _:b504886215 "3"^^ . _:b504886337 . _:b18453270 _:b18453271 . _:b504886214 "3"^^ . _:b504886336 . _:b504886209 "3"^^ . _:b504886339 . . _:b504886192 . _:b504886338 . _:b504886208 "3"^^ . _:b504886310 . _:b504886204 . _:b504886349 . _:b504886211 "3"^^ . . _:b504886210 "3"^^ . _:b504886348 . _:b504886360 . _:b504886225 . _:b504886221 "3"^^ . _:b504886351 . . _:b504886342 . _:b504886220 "3"^^ . _:b504886299 . _:b504886350 . _:b504886331 . _:b504886249 . _:b504886223 "3"^^ . _:b504886345 . _:b504886252 . _:b504886222 "3"^^ . _:b504886344 . . _:b18453242 "the essential regulators of \u201Cstemness,\u201D Nanog, exhibits fluctuating levels of expression and that ES cells expressing low levels of Nanog are predisposed to differentiate, whereas those with high Nanog levels retain their pluripotency (>>43<<). Perhaps, the low and high SC1-expressing NSCs that we observe within the NSC population reflect a similar heterogeneity of these cells with respect to their predisposition to differentiate." . _:b504886217 "3"^^ . _:b504886347 . . _:b504886216 "3"^^ . _:b504886346 . _:b504886391 . . _:b504886337 . _:b504886219 "3"^^ . _:b504886357 . _:b504886218 "3"^^ . _:b504886356 . _:b504886224 . _:b504886229 "3"^^ . _:b504886359 . _:b504886362 . . _:b504886228 "3"^^ . _:b504886358 . _:b504886233 . . _:b504886306 . _:b504886353 . _:b504886231 "3"^^ . _:b504886149 . _:b18453267 . _:b504886230 "3"^^ . _:b504886352 . _:b504886225 "3"^^ . _:b18453260 "cellular development, we recently showed that postmitotic neurons are marked by a different modification\u2014asymmetric dimethylation\u2014of precisely the same arginine residue (H4R3) that is targeted for symmetric dimethylation by PRMT5 (>>35<<). The asymmetric modification (H4R3me2a) is mediated by PRMT1, a type I arginine methyltransferase (39)." . _:b504886355 . . _:b504886224 "3"^^ . _:b504886354 . _:b504886243 . _:b504886227 "3"^^ . _:b504886365 . _:b504886273 . . _:b504886382 . _:b504886226 "3"^^ . _:b18453218 . _:b504886364 . _:b504886237 "2"^^ . _:b504886367 . _:b504886236 "2"^^ . . _:b504886366 . _:b504886385 . _:b504886239 "2"^^ . _:b504886361 . _:b504886238 "2"^^ . _:b504886360 . . _:b504886233 "2"^^ . _:b504886363 . _:b18453238 . _:b504886232 "2"^^ . _:b504886362 . _:b504886235 "2"^^ . _:b504886390 . _:b504886373 . . _:b504886234 "2"^^ . _:b504886372 . _:b504886198 . _:b504886245 "2"^^ . _:b504886375 . _:b504886244 "2"^^ . _:b18453214 "The transitions in NSC fate are likely to be governed by cell lineage-specific transcription factors acting in concert with epigenetic mechanisms (>>9<<\u201314). The latter include post-translational modifications of histones associated with regulatory elements of genes as well as DNA methylation at CpG dinucleotides, which together affect the accessibility of chromatin to the general" . _:b504886374 . _:b504886405 . _:b504886247 "2"^^ . _:b18453217 . . _:b504886369 . _:b504886254 . _:b504886246 "2"^^ . _:b504886368 . _:b504886241 "2"^^ . _:b504886303 . _:b504886371 . . _:b504886240 "2"^^ . _:b504886370 . . _:b504886243 "2"^^ . _:b504886381 . . _:b504886242 "2"^^ . _:b504886380 . . _:b504886288 . _:b504886253 "2"^^ . _:b504886383 . . _:b504886252 "2"^^ . _:b504886366 . . _:b504886382 . _:b504886370 . _:b504886159 . _:b504886255 "2"^^ . _:b504886377 . _:b504886254 "2"^^ . _:b504886222 . _:b504886376 . _:b504886283 . . _:b504886249 "2"^^ . _:b504886379 . _:b18453247 . _:b504886248 "2"^^ . _:b504886378 . _:b504886251 "2"^^ . _:b504886389 . . _:b504886250 "2"^^ . _:b504886388 . _:b504886261 "2"^^ . _:b504886391 . _:b504886307 . . _:b18453259 . _:b504886260 "2"^^ . _:b504886390 . . _:b504886263 "2"^^ . _:b504886385 . . _:b504886221 . _:b504886262 "2"^^ . _:b504886384 . _:b504886257 "2"^^ . _:b504886387 . _:b504886256 "2"^^ . _:b504886386 . _:b504886259 "2"^^ . _:b504886397 . . _:b504886258 "2"^^ . _:b504886383 . . _:b504886396 . _:b504886269 "2"^^ . _:b504886399 . _:b504886268 "2"^^ . . _:b18453214 . _:b504886398 . _:b18453268 "Moreover, it was previously shown that in PC12 cells, which can respond to NGF by differentiating into sympathetic-like neurons, application of NGF increases asymmetric arginine dimethylation of proteins mediated by PRMT1 (49, >>50<<). Taken together, these observations suggest that NSC division and neurogenesis is at least partly regulated by the sequential activation of PRMT5 and PRMT1; high levels of SC1-PRMT5 protein complex during the proliferative stage of" . _:b504886271 "2"^^ . _:b504886393 . _:b504886260 . _:b504886270 "2"^^ . . _:b504886392 . . _:b504886265 "2"^^ . _:b18453232 "Like other PRDM proteins, SC1 possesses a PR/SET domain\u2014a hallmark of lysine histone MTases (HMTases)\u2014that can regulate gene expression by modifying histones in chromatin (>>23<<). Therefore we tested the possibility that SC1 methylates histones as part of its transcriptional repressor function." . . _:b504886395 . _:b504886212 . _:b504886264 "2"^^ . _:b504886394 . . . _:b504886267 "2"^^ . _:b504886372 . _:b504886405 . _:b504886266 "2"^^ . _:b504886404 . _:b504886406 . _:b504886401 . _:b18453214 . . _:b504886400 . _:b18453255 . _:b504886403 . _:b504886402 . . _:b504886213 . _:b504886194 . . . _:b504886150 . . . . _:b504886251 . _:b18453221 "Lineage-specific transcription factors (5) can fine-tune the expression of cell cycle genes and in this way influence the cell fates and division modes of NSCs and consequently their decision either to proliferate or differentiate (16, >>19<<, 20)." . . _:b504886324 . _:b18453257 . _:b18453258 . _:b504886396 . _:b504886397 . _:b504886398 . _:b504886399 . . _:b504886392 . . _:b504886393 . _:b504886394 . _:b504886284 . _:b504886395 . _:b504886388 . _:b504886389 . . _:b504886390 . . _:b504886391 . . _:b504886384 . _:b504886385 . _:b504886386 . . _:b504886387 . _:b504886380 . _:b504886381 . _:b504886181 . _:b504886382 . _:b504886383 . _:b504886376 . _:b504886172 . _:b504886377 . _:b504886378 . _:b504886380 . _:b504886379 . _:b504886372 . _:b504886373 . _:b504886374 . _:b504886375 . _:b504886368 . _:b504886369 . _:b504886370 . _:b504886371 . _:b504886364 . _:b504886365 . _:b504886366 . _:b504886367 . _:b504886360 . . _:b504886361 . . . _:b504886362 . _:b504886363 . _:b504886356 . _:b504886206 . _:b504886357 . _:b504886358 . _:b504886160 . _:b504886359 . _:b504886272 . _:b504886352 . . _:b504886353 . _:b504886354 . _:b504886343 . _:b504886355 . _:b504886275 . _:b504886348 . _:b504886349 . _:b504886350 . _:b504886351 . _:b504886344 . _:b504886345 . _:b504886346 . _:b504886347 . . _:b504886340 . . _:b504886341 . . _:b504886342 . _:b504886343 . . _:b504886336 . _:b504886337 . _:b504886289 . _:b504886338 . _:b504886339 . _:b504886332 . _:b504886333 . . _:b504886334 . _:b504886335 . _:b504886328 . _:b504886329 . _:b504886330 . _:b504886331 . _:b504886324 . _:b504886325 . _:b504886326 . _:b504886327 . . _:b504886320 . _:b504886321 . _:b504886322 . _:b504886323 . _:b504886316 . _:b504886317 . _:b504886318 . _:b504886298 . _:b504886319 . _:b504886312 . _:b504886313 . . _:b504886314 . _:b504886315 . _:b504886147 . _:b18453218 "factors, cell cycle parameters such as the length of specific cell cycle stages play an important role in controlling NSC proliferation and differentiation (5, 6, 15\u201317), and these parameters change during cortical development (>>18<<). Lineage-specific transcription factors (5) can fine-tune the expression of cell cycle genes and in this way influence the cell fates and division modes of NSCs and consequently their decision either to proliferate or differentiate (16," . _:b504886308 . _:b504886309 . _:b18453207 . _:b504886310 . _:b504886311 . _:b504886304 . _:b504886305 . . _:b504886176 . _:b504886306 . _:b504886229 . _:b504886307 . _:b504886300 . _:b504886301 . . _:b504886302 . _:b504886303 . _:b504886296 . . . _:b504886297 . _:b18453247 "For example, the changing cell cycle parameters and kinetics during precursor cell differentiation may be a common mechanism that contributes to the developmental decisions made by these cells (>>16<<\u201319). Precise control of cell cycle progression is one of the critical components of precursor cell differentiation, and changes in the cell cycle parameters are likely to regulate various aspects of the responsiveness of these cells to" . _:b504886298 . _:b504886299 . _:b504886292 . _:b504886293 . _:b504886188 . _:b504886294 . _:b504886295 . _:b18453225 "The PR domains are similar to but distinct from the SET domains found in many histone lysine methyltransferases (MTases) (>>23<<). PRDM proteins are either epigenetic modifiers in their own right or else they recruit third party chromatin modifiers\u2014e.g., histone deacetylases (HDACs), histone lysine MTases, or histone arginine MTases\u2014to regulate cell type-specific" . _:b504886288 . _:b504886289 . _:b504886290 . _:b504886191 . _:b504886291 . _:b18453235 "Therefore, we asked whether PRMT5, a type II PRMT that is known to catalyze H4R3me2s (39, >>40<<), might interact with SC1 protein." . _:b504886284 . _:b504886285 . _:b504886286 . _:b504886287 . _:b504886280 . _:b504886353 . _:b504886281 . _:b504886282 . _:b504886283 . . _:b504886276 . _:b504886277 . . _:b504886364 . _:b504886278 . _:b504886279 . _:b504886140 . _:b504886272 . _:b18453258 "An intriguing aspect of PRMT5 biology is its dynamic subcellular localization and the recent observation that during ES cell development PRMT5 mediates methylation of R3 on cytoplasmic histone H2A, thereby preserving ES cell stemness (>>41<<). We also detect high levels of both SC1 and PRMT5 in the cytoplasm of neuroepithelial cells in the developing cerebral cortex, suggesting that SC1-PRMT5 might methylate newly synthesized cytosolic histones during the S phase, prior to" . _:b504886273 . _:b504886274 . _:b504886275 . _:b504886195 . _:b504886346 . . _:b504886311 . _:b504886165 . . . . _:b504886208 . . . . _:b504886238 . . . _:b504886161 . _:b18453237 . . . . _:b18453227 . _:b504886239 . _:b18453226 . . . _:b504886277 . _:b504886404 . _:b504886405 . _:b504886406 . _:b18453253 "Blimp1, like SC1, favors the preservation of the undifferentiated cellular state in primordial germ cells and, also like SC1, exerts its action through recruitment of PRMT5 (>>25<<)." . _:b504886400 . _:b504886401 . _:b504886402 . _:b504886403 . _:b504886200 . . . _:b18453263 "Because both PRMT5 and SC1 have been found in association with HDAC1 and HDAC2 (>>33<<, 39, 40), it is possible that SC1 might be a common component of the repressive chromatin remodeling complexes during early neural development and that the principal role of SC1 in such complexes might be to provide targeting specificity" . _:b504886242 . . _:b504886381 . . _:b18453210 . . . _:b18453231 "The different cell types were generated in the appropriate temporal order (2, >>37<<): Nestin+ precursors were present from the outset, followed by TuJ1+ neurons, GFAP+ astrocytes, and O4+ OLPs at progressively longer culture periods.3 We found that immediately after plating, Nestin+ NSCs could be characterized as either" . . . . _:b504886316 . . . _:b504886163 . _:b504886328 . . . . _:b18453237 "Previously, we showed that SC1 controls cellular proliferation by down-regulating promitotic genes, e.g., cycB was one of the transcriptional targets of SC1-mediated repression (>>33<<). Therefore, we considered the possibility that the SC1-PRMT5 complex might regulate the timing of neurogenesis in developing NSCs in part by regulating their cell cycle parameters." . _:b504886167 . . _:b18453273 "V. Chao, 1:40 (>>33<<)), anti-PRMT5 (Upstate Biotech, 1:100), anti-H4R3me2s (Abcam, 1:" . . _:b504886144 . _:b504886154 . _:b504886356 . _:b504886218 . . . _:b504886199 .