The Basic Helix-Loop-Helix Genes Hesr1/Hey1 and Hesr2/Hey2 Regulate Maintenance of Neural Precursor Cells in the Brain

Neural precursor cells proliferate in the ventricular zone while giving rise to neurons of deep layers first, then those of the superficial layers, and lastly, glial cells in the brain. Thus, it is essential to maintain neural precursor cells until late stages of neural development for generation of a wide variety of cell types. Here, we found that the Hes-related basic helix-loop-helix (bHLH) genes Hesr1/Hey1 and Hesr2/Hey2 are expressed in the ventricular zone, which contains neural precursor cells. Misexpression of Hesr1 and Hesr2 by electroporation in mouse brain at embryonic day 13.5 transiently maintains neural precursor cells and thereby increases late-born neurons, which are located in the superficial layers. In contrast, misexpression of the genes at later stages inhibits neurogenesis and promotes generation of astroglial cells. In transient transfection assay with cultured cells, both Hesr1 and Hesr2 inhibit transcription induced by the neuronal bHLH genes Mash1 and Math3. These results indicate that Hesr1 and Hesr2 negatively regulate neuronal bHLH genes, promote maintenance of neural precursor cells, and increase late-born cell types in the developing brain. Neural precursor cells proliferate in the ventricular zone while giving rise to neurons of deep layers first, then those of the superficial layers, and lastly, glial cells in the brain. Thus, it is essential to maintain neural precursor cells until late stages of neural development for generation of a wide variety of cell types. Here, we found that the Hes-related basic helix-loop-helix (bHLH) genes Hesr1/Hey1 and Hesr2/Hey2 are expressed in the ventricular zone, which contains neural precursor cells. Misexpression of Hesr1 and Hesr2 by electroporation in mouse brain at embryonic day 13.5 transiently maintains neural precursor cells and thereby increases late-born neurons, which are located in the superficial layers. In contrast, misexpression of the genes at later stages inhibits neurogenesis and promotes generation of astroglial cells. In transient transfection assay with cultured cells, both Hesr1 and Hesr2 inhibit transcription induced by the neuronal bHLH genes Mash1 and Math3. These results indicate that Hesr1 and Hesr2 negatively regulate neuronal bHLH genes, promote maintenance of neural precursor cells, and increase late-born cell types in the developing brain. Neural development involves the following three sequential processes: expansion of neural precursor cells, neurogenesis, and gliogenesis (1Schuurmans C. Guillemot F. Curr. Opin. Neurobiol. 2002; 12: 26-34Crossref PubMed Scopus (289) Google Scholar, 2Panchision D.M. McKay R.D.G. Curr. Opin. Genet. Dev. 2002; 12: 478-487Crossref PubMed Scopus (172) Google Scholar). In mice, neural precursor cells proliferate without giving rise to neurons until mid-gestation. Then, neurogenesis starts and continues until around birth. Differentiating neurons migrate out of the ventricular zone into the outer regions, forming the cortical plate. During this process, newly born neurons migrate through the layers of older neurons to form more superficial layers, thereby making the inside-out pattern. Gliogenesis starts before birth, but the majority of glial cells such as astrocytes are generated after neurogenesis. It has been shown that these developmental processes are regulated by multiple basic helix-loop-helix (bHLH) 1The abbreviations used are: bHLH, basic helix-loop-helix; TUNEL, terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling; E (e.g. E13.5), embryonic day; P (e.g. P1), postnatal day; GFP, green fluorescent protein; EGFP, enhanced green fluorescent protein; GFAP, glial fibrillary acidic protein; MAP2, microtubule-associated protein-2. genes (3Kageyama R. Nakanishi S. Curr. Opin. Genet. Dev. 1997; 7: 659-665Crossref PubMed Scopus (329) Google Scholar, 4Lee J.E. Curr. Opin. Neurobiol. 1997; 7: 13-20Crossref PubMed Scopus (440) Google Scholar, 5Bertrand N. Castro D.S. Guillemot F. Nat. Rev. Neurosci. 2002; 3: 517-530Crossref PubMed Scopus (1164) Google Scholar, 6Ross S.E. Greenberg M.E. Stiles C.D. Neuron. 2003; 39: 13-25Abstract Full Text Full Text PDF PubMed Scopus (511) Google Scholar). The bHLH genes Hes1 and Hes5 encode transcriptional repressors, and misexpression of the genes at early stages maintains neural precursor cells and increases late-born neurons (7Sasai Y. Kageyama R. Tagawa Y. Shigemoto R. Nakanishi S. Genes Dev. 1992; 6: 2620-2634Crossref PubMed Scopus (583) Google Scholar, 8Akazawa C. Sasai Y. Nakanishi S. Kageyama R. J. Biol. Chem. 1992; 267: 21879-21885Abstract Full Text PDF PubMed Google Scholar, 9Ishibashi M. Moriyoshi K. Sasai Y. Shiota K. Nakanishi S. Kageyama R. EMBO J. 1994; 13: 1799-1805Crossref PubMed Scopus (339) Google Scholar, 10Ishibashi M. Ang S.-L. Shiota K. Nakanishi S. Kageyama R. Guillemot F. Genes Dev. 1995; 9: 3136-3148Crossref PubMed Scopus (428) Google Scholar, 11Tomita K. Ishibashi M. Nakahara K. Ang S.-L. Nakanishi S. Guillemot F. Kageyama R. Neuron. 1996; 16: 723-734Abstract Full Text Full Text PDF PubMed Scopus (281) Google Scholar, 12Nakamura Y. Sakakibara S. Miyata T. Ogawa M. Shimazaki T. Weiss S. Kageyama R. Okano H. J. Neurosci. 2000; 20: 283-293Crossref PubMed Google Scholar, 13Ohtsuka T. Sakamoto M. Guillemot F. Kageyama R. J. Biol. Chem. 2001; 276: 30467-30474Abstract Full Text Full Text PDF PubMed Scopus (339) Google Scholar, 14Castella P. Wagner J.A. Caudy M. J. Neurosci. Res. 1999; 56: 229-240Crossref PubMed Scopus (56) Google Scholar). However, at later stages, misexpression of Hes1 and Hes5 results in an increase in the number of glial cells (13Ohtsuka T. Sakamoto M. Guillemot F. Kageyama R. J. Biol. Chem. 2001; 276: 30467-30474Abstract Full Text Full Text PDF PubMed Scopus (339) Google Scholar, 15Hojo M. Ohtsuka T. Hashimoto N. Gradwohl G. Guillemot F. Kageyama R. Development. 2000; 127: 2515-2522PubMed Google Scholar, 16Furukawa T. Mukherjee S. Bao Z.-Z. Morrow E.M. Cepko C.L. Neuron. 2000; 26: 383-394Abstract Full Text Full Text PDF PubMed Scopus (433) Google Scholar). Thus, Hes1 and Hes5 misexpression leads to different outcomes, depending on the developmental stages. In contrast, neuronal bHLH genes such as Mash1, Math3, and Neurogenin encode transcriptional activators and promote neurogenesis (17Guillemot F. Lo L.-C. Johnson J.E. Auerbach A. Anderson D.J. Joyner A.L. Cell. 1993; 75: 463-476Abstract Full Text PDF PubMed Scopus (928) Google Scholar, 18Ma Q. Kintner C. Anderson D.J. Cell. 1996; 87: 43-52Abstract Full Text Full Text PDF PubMed Scopus (720) Google Scholar, 19Takebayashi K. Takahashi S. Yokota C. Tsuda H. Nakanishi S. Asashima M. Kageyama R. EMBO J. 1997; 16: 384-395Crossref PubMed Scopus (132) Google Scholar, 20Tomita K. Moriyoshi K. Nakanishi S. Guillemot F. Kageyama R. EMBO J. 2000; 19: 5460-5472Crossref PubMed Scopus (244) Google Scholar, 21Nieto M. Schuurmans C. Britz O. Guillemot F. Neuron. 2001; 29: 401-413Abstract Full Text Full Text PDF PubMed Scopus (434) Google Scholar, 22Sun Y. Nadal-Vicens M. Misono S. Lin M.Z. Zubiaga A. Hua X. Fan G. Greenberg M.E. Cell. 2001; 104: 365-376Abstract Full Text Full Text PDF PubMed Scopus (662) Google Scholar, 23Cai L. Morrow E.M. Cepko C.L. Development. 2000; 127: 3021-3030PubMed Google Scholar, 24Bae S.-K. Bessho Y. Hojo M. Kageyama R. Development. 2000; 127: 2933-2943PubMed Google Scholar, 25Mizuguchi R. Sugimori M. Takebayashi H. Kosako H. Nagao M. Yoshida S. Nabeshima Y. Shimamura K. Nakafuku M. Neuron. 2001; 31: 757-771Abstract Full Text Full Text PDF PubMed Scopus (369) Google Scholar, 26Novitch B.G. Chen A.I. Jessell T.M. Neuron. 2001; 31: 773-789Abstract Full Text Full Text PDF PubMed Scopus (504) Google Scholar, 27Zhou Q. Anderson D.J. Cell. 2002; 109: 61-73Abstract Full Text Full Text PDF PubMed Scopus (844) Google Scholar). Inactivation of neuronal bHLH genes impairs neurogenesis, and the cells that are inhibited from neuronal differentiation remain as neural precursor cells initially but, at later stages, prematurely differentiate into astrocytes (20Tomita K. Moriyoshi K. Nakanishi S. Guillemot F. Kageyama R. EMBO J. 2000; 19: 5460-5472Crossref PubMed Scopus (244) Google Scholar, 21Nieto M. Schuurmans C. Britz O. Guillemot F. Neuron. 2001; 29: 401-413Abstract Full Text Full Text PDF PubMed Scopus (434) Google Scholar). Interestingly, these phenotypes of neuronal bHLH gene deficiency are similar to those of misexpression of Hes1 and Hes5, which also initially maintain neural precursor cells but later promote gliogenesis (13Ohtsuka T. Sakamoto M. Guillemot F. Kageyama R. J. Biol. Chem. 2001; 276: 30467-30474Abstract Full Text Full Text PDF PubMed Scopus (339) Google Scholar). Because Hes1 and Hes5 can functionally antagonize neuronal bHLH genes (7Sasai Y. Kageyama R. Tagawa Y. Shigemoto R. Nakanishi S. Genes Dev. 1992; 6: 2620-2634Crossref PubMed Scopus (583) Google Scholar, 8Akazawa C. Sasai Y. Nakanishi S. Kageyama R. J. Biol. Chem. 1992; 267: 21879-21885Abstract Full Text PDF PubMed Google Scholar), it is likely that misexpression of Hes1 or Hes5 leads to the situations similar to neuronal bHLH gene deficiency. Thus, antagonistic regulation between multiple bHLH genes is important for timing the processes of precursor expansion, neurogenesis, and gliogenesis. Despite these extensive studies, mutational analyses of the bHLH genes explain only a portion of the neural development, suggesting that other uncharacterized bHLH genes also should be involved in such processes. For example, although the lack of Hes1 and Hes5 impairs maintenance of neural precursor cells, these cells still proliferate at a slower rate without losing the multipotentiality to differentiate into neurons and glial cells (13Ohtsuka T. Sakamoto M. Guillemot F. Kageyama R. J. Biol. Chem. 2001; 276: 30467-30474Abstract Full Text Full Text PDF PubMed Scopus (339) Google Scholar, 28Ohtsuka T. Ishibashi M. Gradwohl G. Nakanishi S. Guillemot F. Kageyama R. EMBO J. 1999; 18: 2196-2207Crossref PubMed Google Scholar), which suggests that other genes should be involved in maintenance of this cell type. Recent studies demonstrated that Hes-related bHLH genes, termed Hesr genes (also referred to as Hey/HRT/CHF/HERP/gridlock), are expressed in the developing brain and retina (29Kokubo H. Lun Y. Johnson R.L. Biochem. Biophys. Res. Commun. 1999; 260: 459-465Crossref PubMed Scopus (126) Google Scholar, 30Leimeister C. Externbrink A. Klamt B. Gessler M. Mech. 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Here, we found that Hesr1 and Hesr2 are expressed in the developing brain and that misexpression of the Hesr genes transiently increases neural precursor cells and thereby promotes generation of late-born cell types. Hesr1 and Hesr2 inhibit the neuronal bHLH genes Mash1 and Math3, Hes1 and These results indicate that Hesr genes are of neuronal bHLH genes and promote maintenance of neural precursor cells. of Hesr1 and of Hesr2 from mouse retina used as T. S.-K. T. C. G. K. Bessho Y. Hashimoto N. Kageyama R. J. Neurosci. 2001; PubMed Google Scholar). from mouse on a and to a at in and and at in and In to and of Hesr1 and Hesr2 T. S.-K. T. C. G. K. Bessho Y. Hashimoto N. Kageyama R. J. Neurosci. 2001; PubMed Google Scholar), in In as C. Sasai Y. Nakanishi S. Kageyama R. J. Biol. Chem. 1992; 267: 21879-21885Abstract Full Text PDF PubMed Google Scholar). in for three with for and then three with for at in at in for in and at in For in and and a with an In Hesr1 and Hesr2 into the of which of genes as as of enhanced green fluorescent through the from the terminal with M. Ohtsuka T. Hashimoto N. Gradwohl G. Guillemot F. Kageyama R. Development. 2000; 127: 2515-2522PubMed Google Scholar). For the of and a to in as (13Ohtsuka T. Sakamoto M. Guillemot F. Kageyama R. J. Biol. Chem. 2001; 276: 30467-30474Abstract Full Text Full Text PDF PubMed Scopus (339) Google Scholar). The in as a through the with a into the of of also with the in cells can be more electroporation of with out as (13Ohtsuka T. Sakamoto M. Guillemot F. Kageyama R. J. Biol. Chem. 2001; 276: 30467-30474Abstract Full Text Full Text PDF PubMed Scopus (339) Google Scholar). the of the mouse and to in The in in for at in in and in and In the of the cells initially to be three with in and for and then with The used are as mouse mouse mouse and mouse these and nick end assay as in with and at for and with a For cells in the of and cells for and cells for of Hesr1 and Hesr2 at increases astrocytes at at and the of the cells at electroporation of of the cells located in the cortical and expressed the neuronal of the is shown in the in A. electroporation of and of the cells located in the zone and for suggesting that misexpression of Hesr1 or Hesr2 increases of the is shown in the in E and H. is in the cell and of the cell types in of three are shown with S.E. and of of brain cells, the brain as J. K. T. Kageyama R. Development. 2001; PubMed Google Scholar). The brain with and in for at and of the The cells in and on and for at in the cells with for and to the gene the of the with of the S.-K. Bessho Y. Hojo M. Kageyama R. Development. 2000; 127: 2933-2943PubMed Google Scholar). of Hesr1 and Hesr2 into the for Mash1, Math3, and (7Sasai Y. Kageyama R. Tagawa Y. Shigemoto R. Nakanishi S. Genes Dev. 1992; 6: 2620-2634Crossref PubMed Scopus (583) Google Scholar). The and the with the transfection into cells, which in at a of of the the gene the of the also as an to the transfection the cells and the a of Hesr1 and Hesr2 in the gene in the brain by During the from embryonic day to both Hesr1 and Hesr2 are expressed is Hesr1 and Hesr2 by in both Hesr1 and Hesr2 are expressed in the ventricular zone of the developing brain and Hesr1 is the brain Hesr2 is to the of the brain Hesr1 and Hesr2 are expressed at a in the ventricular zone and at a in the cortical this Hesr2 is also in the in to the of the brain Hesr1 and Hesr2 is also in the ventricular zone of the and In contrast, the and These results indicate that Hesr1 and Hesr2 are expressed by cells in the developing brain. Misexpression of Hesr1 and Hesr2 at Neural at the of Hesr1 and Hesr2 in neural development, we the genes in the developing mouse brain by the which also as a The into the of mouse in and electroporation this the transiently into the ventricular cells on the then to in later from the and the of the cells electroporation of at the majority of the cells out of the ventricular zone and located in the zone and the cortical at and In those in the cortical expressed the neuronal and that of the cells into neurons the of In contrast, electroporation of or at the majority of cells in the ventricular zone at and these cells for and but expressed a of neural precursor cells and in and of cell in demonstrated that of the cells neurons, only of the or cells These results indicate that Hesr1 and Hesr2 inhibit neurogenesis and maintain neural precursor cells also assay to cell is induced by Hesr However, we in the cell and Thus, of neurogenesis by Hesr genes is to neuronal Misexpression of Hesr2 at the Hesr genes maintain neural precursor cells in the we the ventricular zone is by by electroporation into the of the at and the ventricular zone at by the Hes5 and the Hesr2 in the of the the Hesr2 at the and In this both Hes5 and with the brain and These results indicate that misexpression of Hesr2 the ventricular zone by neural precursor cells. Misexpression of Hesr1 and Hesr2 at at the later of misexpression of Hesr1 and The at and the of the cells at postnatal day Hesr genes this at is more Hesr (13Ohtsuka T. Sakamoto M. Guillemot F. Kageyama R. J. Biol. Chem. 2001; 276: 30467-30474Abstract Full Text Full Text PDF PubMed Scopus (339) Google Scholar). Thus, this to the of the cells after Hesr the majority of the cells found in the cortical and expressed the late neuronal in to at or by of the cells found in both the cortical and the zone at and The cells found in the cortical expressed MAP2, those in the zone and These results indicate that of the cells, which as at by misexpression of Hesr1 and into neurons at However, these cells located in more superficial layers those with and suggesting that misexpression of Hesr1 and Hesr2 the of with this of the cells still and in to the cells, which expressed These results indicate that misexpression of Hesr1 and Hesr2 at increases late-born neurons at Misexpression of Hesr1 and Hesr2 at at of Hesr1 and maintenance of neural precursor cells and increase of late-born neurons, are similar to those of Hes1 and Hes5 (13Ohtsuka T. Sakamoto M. Guillemot F. Kageyama R. J. Biol. Chem. 2001; 276: 30467-30474Abstract Full Text Full Text PDF PubMed Scopus (339) Google Scholar). studies demonstrated that at later stages, Hes1 and Hes5 promote gliogenesis in the brain (13Ohtsuka T. Sakamoto M. Guillemot F. Kageyama R. J. Biol. Chem. 2001; 276: 30467-30474Abstract Full Text Full Text PDF PubMed Scopus (339) Google Scholar). Hesr1 and Hesr2 at and the cell at by of the cells into the cortical and into neurons In contrast, or by of the cells in the zone and into astrocytes E and of cell in that of the cells neurons, the majority of or cells astrocytes is in the cell between these that cell for the by Hesr1 and Hesr2 and These results indicate that misexpression of Hesr1 or Hesr2 at inhibits neurogenesis and promotes gliogenesis. the of Hesr1 and Hesr2 misexpression with an we electroporation at and the at cells to the and with and this neurons and astrocytes can be at more of the cells into neurons, only astrocytes at In contrast, or at of the cells into astrocytes the of neurons and astrocytes by this are different from those by in both the of neurons and increase of astrocytes by Hesr also assay to cell is induced by misexpression of Hesr1 and However, we or of cell Thus, Hesr1 and Hesr2 inhibit neurogenesis without of These results that the that should differentiate into neurons at are inhibited from neuronal differentiation by Hesr1 and Hesr2 and remain as until gliogenesis of neurogenesis and gliogenesis from neural precursor cells. of and at and the of neurons and astrocytes from cells at as in the for of neurons and astrocytes with S.E. results of are Hesr1 and Hesr2 bHLH that Hesr1 and Hesr2 transiently maintain neural precursor cells and thereby increase late-born cell types such as These phenotypes are similar to those of of neuronal bHLH genes such as Mash1 and (20Tomita K. Moriyoshi K. Nakanishi S. Guillemot F. Kageyama R. EMBO J. 2000; 19: 5460-5472Crossref PubMed Scopus (244) Google Scholar, 21Nieto M. Schuurmans C. Britz O. Guillemot F. Neuron. 2001; 29: 401-413Abstract Full Text Full Text PDF PubMed Scopus (434) Google Scholar). the of Hesr1 and Hesr2 on Mash1 and Math3. transient transfection assay with cells, both Mash1 and induced transcription from the and the also and as (7Sasai Y. Kageyama R. Tagawa Y. Shigemoto R. Nakanishi S. Genes Dev. 1992; 6: 2620-2634Crossref PubMed Scopus (583) Google Scholar, J.E. T. Anderson D.J. S. A. 1992; PubMed Scopus Google Scholar). In contrast, both Hesr1 and Hesr2 inhibited and transcription and These results indicate that Hesr1 and Hesr2 functionally antagonize neuronal bHLH In this Hesr1 Hesr2 transcription from the and These results with the that Hesr1 and Hesr2 to T. C. S. G. L. Y. Biol. 2001; PubMed Scopus Google Scholar, O. Nakagawa M. H. T. Srivastava D. Olson E.N. S. A. 2000; PubMed Scopus Google Scholar). Hesr1 and Hesr2 Neural in the precursor cells rise to different types of cells as development by For example, late only rise to late-born cell types Development. 2000; 127: PubMed Google Scholar). Thus, it is important to maintain neural precursor cells until late stages of neural development to a wide variety of cells. studies that the bHLH genes Hes1 and Hes5 an important in maintenance of neural precursor cells (13Ohtsuka T. Sakamoto M. Guillemot F. Kageyama R. J. Biol. Chem. 2001; 276: 30467-30474Abstract Full Text Full Text PDF PubMed Scopus (339) Google Scholar, 28Ohtsuka T. Ishibashi M. Gradwohl G. Nakanishi S. Guillemot F. Kageyama R. EMBO J. 1999; 18: 2196-2207Crossref PubMed Google Scholar). However, neural precursor cells both Hes1 and Hes5 still proliferate without losing multipotentiality to differentiate into neurons and glial cells (13Ohtsuka T. Sakamoto M. Guillemot F. Kageyama R. J. Biol. Chem. 2001; 276: 30467-30474Abstract Full Text Full Text PDF PubMed Scopus (339) Google Scholar), that other genes Hes1 and Hes5 for the of neural precursor cells. Here, we that bHLH genes, Hesr1 and are expressed in the ventricular zone, inhibit neuronal bHLH gene and promote maintenance of neural precursor cells. a Hesr1 and Hesr2 increase later born cell neurons of more superficial layers of the cortical at and astrocytes at a assay that Hesr1 and Hesr2 of early born cell types. It is likely that the precursor cells that should differentiate into early cell types are inhibited from differentiation by misexpression of Hesr1 and Hesr2 and the late cell Thus, Hesr1 and Hesr2 an important in of late-born cell types by neural precursor cells. Recent studies demonstrated that M. A. K. N. A. C. Curr. Biol. 2002; 12: Full Text Full Text PDF PubMed Scopus Google Scholar, J. A. Curr. Biol. 2002; 12: Full Text Full Text PDF PubMed Scopus Google Scholar, Y. H. R. M.T. S. A. 2002; PubMed Scopus Google Scholar). However, neural are in these It is that Hesr1 Hesr2 for maintenance of neural precursor cells in such It is also that Hes1 and Hes5 Hesr2 for neural Hesr1 and Hesr2 bHLH Hesr1 and Hesr2 inhibit the transcriptional of the neuronal bHLH Mash1 and Math3. It has been shown that neuronal bHLH genes the of neurogenesis and of gliogenesis (20Tomita K. Moriyoshi K. Nakanishi S. Guillemot F. Kageyama R. EMBO J. 2000; 19: 5460-5472Crossref PubMed Scopus (244) Google Scholar, 21Nieto M. Schuurmans C. Britz O. Guillemot F. Neuron. 2001; 29: 401-413Abstract Full Text Full Text PDF PubMed Scopus (434) Google Scholar, 22Sun Y. Nadal-Vicens M. Misono S. Lin M.Z. Zubiaga A. Hua X. Fan G. Greenberg M.E. Cell. 2001; 104: 365-376Abstract Full Text Full Text PDF PubMed Scopus (662) Google Scholar). Inactivation of neuronal bHLH genes impairs neurogenesis and leads to maintenance of neural precursor cells at early stages and of gliogenesis at later stages (20Tomita K. Moriyoshi K. Nakanishi S. Guillemot F. Kageyama R. EMBO J. 2000; 19: 5460-5472Crossref PubMed Scopus (244) Google Scholar, 21Nieto M. Schuurmans C. Britz O. Guillemot F. Neuron. 2001; 29: 401-413Abstract Full Text Full Text PDF PubMed Scopus (434) Google Scholar). These phenotypes are similar to those of Hesr1 and Hesr2 Thus, it is likely that the of Hesr1 and Hesr2 are to of the of neuronal bHLH genes, although other such as of or gene by Hesr are also Interestingly, the of Hesr1 and Hesr2 are similar to those of (13Ohtsuka T. Sakamoto M. Guillemot F. Kageyama R. J. Biol. Chem. 2001; 276: 30467-30474Abstract Full Text Full Text PDF PubMed Scopus (339) Google Scholar, N. G. Neuron. 2000; 26: Full Text Full Text PDF PubMed Scopus Google Scholar, K. F. Takahashi J. K. H. T. Neuron. 2001; 29: Full Text Full Text PDF PubMed Scopus Google Scholar, S. F. M. Development. 2002; PubMed Google Scholar, S. T. D. A. D. Genes Dev. 2002; 16: PubMed Scopus Google Scholar). is a and by the of is from the into the and a with the T. Genes 1996; PubMed Scopus Google Scholar, S. M.D. Science. 1999; PubMed Scopus Google Scholar). of and Hesr genes T. G. T. L. Y. Biol. 2001; PubMed Scopus Google Scholar, O. Nakagawa M. H. T. Srivastava D. Olson E.N. S. A. 2000; PubMed Scopus Google Scholar, Gessler M. Biochem. Biophys. Res. Commun. 2000; 275: PubMed Scopus Google Scholar). Thus, it is likely that Hesr and genes of to inhibit neuronal bHLH It has been shown that the timing of the developmental such as neurogenesis, and is in neural precursor cells X. Q. A. S. Neuron. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). neural precursor cells in the timing of the differentiation of X. Q. A. S. Neuron. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). The for this is but it is that the of multiple bHLH genes such as and Mash1 be in neural precursor cells, although this is to be In these cells, antagonistic regulation between and neuronal bHLH genes the timing of neurogenesis. for the is of of In early is by in late the is T. K. M. A. M. N. M. T. Dev. Cell. 2002; Full Text Full Text PDF Scopus Google Scholar). of early with a leads to gliogenesis T. K. M. A. M. N. M. T. Dev. Cell. 2002; Full Text Full Text PDF Scopus Google Scholar). Thus, the is likely to to the timing of gliogenesis. of the bHLH gene and be important for the timing of cell of Hesr1 and Hesr2 in the the Hesr1 and Hesr2 Hesr2 is expressed by glial cells, Hesr1 is expressed by other cell types T. S.-K. T. C. G. K. Bessho Y. Hashimoto N. Kageyama R. J. Neurosci. 2001; PubMed Google Scholar). although Hesr2 promotes generation of glial cells, Hesr1 T. S.-K. T. C. G. K. Bessho Y. Hashimoto N. Kageyama R. J. Neurosci. 2001; PubMed Google Scholar). Hesr1 gliogenesis neurogenesis in the Thus, Hesr1 and Hesr2 different in the In contrast, in the Hesr1 and Hesr2 to the and we in the between the It to be the genes such in the is the of It has been that the of Hesr be important for the of the a similar at the which is essential for Hesr1 and is in the the that different with Hesr1 and studies of are to the by which Hesr regulate gene for