Gene Symbol: Neurod4
Description: neurogenic differentiation 4
Alias: AI846749, ATH-3, Atoh3, MATH-3, Math3, bHLHa4, neurogenic differentiation factor 4, atonal homolog 3, helix-loop-helix protein mATH-3
Species: mouse
Products:     Neurod4

Top Publications

  1. Pattyn A, Hirsch M, Goridis C, Brunet J. Control of hindbrain motor neuron differentiation by the homeobox gene Phox2b. Development. 2000;127:1349-58 pubmed
    ..Thus, the loss of function of Phox2b in hindbrain motor neurons exemplifies a novel control point in the generation of CNS neurons. ..
  2. Hatakeyama J, Tomita K, Inoue T, Kageyama R. Roles of homeobox and bHLH genes in specification of a retinal cell type. Development. 2001;128:1313-22 pubmed
    Previous analysis of mutant mice has revealed that the bHLH genes Mash1 and Math3, and the homeobox gene Chx10 are essential for generation of bipolar cells, the interneurons present in the inner nuclear layer of the retina...
  3. Li S, Mo Z, Yang X, Price S, Shen M, Xiang M. Foxn4 controls the genesis of amacrine and horizontal cells by retinal progenitors. Neuron. 2004;43:795-807 pubmed
    ..controls the formation of amacrine and horizontal cells by activating the expression of the retinogenic factors Math3, NeuroD1, and Prox1...
  4. Inoue T, Hojo M, Bessho Y, Tano Y, Lee J, Kageyama R. Math3 and NeuroD regulate amacrine cell fate specification in the retina. Development. 2002;129:831-42 pubmed
    The basic helix-loop-helix genes Math3 and NeuroD are expressed by differentiating amacrine cells, retinal interneurons...
  5. Takebayashi K, Takahashi S, Yokota C, Tsuda H, Nakanishi S, Asashima M, et al. Conversion of ectoderm into a neural fate by ATH-3, a vertebrate basic helix-loop-helix gene homologous to Drosophila proneural gene atonal. EMBO J. 1997;16:384-95 pubmed
  6. Kapali J, Kabat B, Schmidt K, Stallings C, Tippy M, Jung D, et al. Foxo1 Is Required for Normal Somatotrope Differentiation. Endocrinology. 2016;157:4351-4363 pubmed
    ..of FOXO1 regulation of somatotrope differentiation may involve the basic helix-loop-helix transcription factor, Neurod4, which has been implicated in somatotrope differentiation and is significantly reduced in Foxo1?pit ..
  7. Oron Karni V, Farhy C, Elgart M, Marquardt T, Remizova L, Yaron O, et al. Dual requirement for Pax6 in retinal progenitor cells. Development. 2008;135:4037-4047 pubmed publisher
    ..Together, these data suggest an intricate dual role for Pax6 in retinal neurogenesis, while pointing to the cryptic divergence of RPCs into distinct progenitor pools. ..
  8. Gavalas A, Ruhrberg C, Livet J, Henderson C, Krumlauf R. Neuronal defects in the hindbrain of Hoxa1, Hoxb1 and Hoxb2 mutants reflect regulatory interactions among these Hox genes. Development. 2003;130:5663-79 pubmed
    ..Therefore, we have delineated the functional requirements in hindbrain neuronal patterning that follow the establishment of the genetic regulatory hierarchy between Hoxa1, Hoxb1 and Hoxb2. ..
  9. Davenne M, Maconochie M, Neun R, Pattyn A, Chambon P, Krumlauf R, et al. Hoxa2 and Hoxb2 control dorsoventral patterns of neuronal development in the rostral hindbrain. Neuron. 1999;22:677-91 pubmed

More Information


  1. Dykes I, Tempest L, Lee S, Turner E. Brn3a and Islet1 act epistatically to regulate the gene expression program of sensory differentiation. J Neurosci. 2011;31:9789-99 pubmed publisher to developmentally repress neurogenic bHLH genes, and in vivo chromatin immunoprecipitation shows that Islet1 binds to a known Brn3a-regulated enhancer in the neurod4 gene, suggesting a mechanism of interaction between these genes.
  2. Qu J, Li X, Novitch B, Zheng Y, Kohn M, Xie J, et al. PAK4 kinase is essential for embryonic viability and for proper neuronal development. Mol Cell Biol. 2003;23:7122-33 pubmed
    ..PAK4-null embryos also had defects in proper folding of the caudal portion of the neural tube, suggesting an important role for PAK4 in neural tube development. ..
  3. Asprer J, Lee B, Wu C, Vadakkan T, Dickinson M, Lu H, et al. LMO4 functions as a co-activator of neurogenin 2 in the developing cortex. Development. 2011;138:2823-32 pubmed publisher
    ..Our results indicate that LMO4 promotes the acquisition of cortical neuronal identities by forming a complex with NGN2 and subsequently activating NGN2-dependent gene expression. ..
  4. Bharti K, Gasper M, Ou J, Brucato M, Clore Gronenborn K, Pickel J, et al. A regulatory loop involving PAX6, MITF, and WNT signaling controls retinal pigment epithelium development. PLoS Genet. 2012;8:e1002757 pubmed publisher
    ..The results suggest that careful manipulation of the Pax6 regulatory circuit may facilitate the generation of retinal and pigment epithelium cells from embryonic or induced pluripotent stem cells. ..
  5. Ma Q, Deng P, Zhu G, Liu C, Zhang L, Zhou Z, et al. Extremely low-frequency electromagnetic fields affect transcript levels of neuronal differentiation-related genes in embryonic neural stem cells. PLoS ONE. 2014;9:e90041 pubmed publisher
    ..induced to differentiation, real-time PCR results showed a down-regulation of Sox2 and up-regulation of Math1, Math3, Ngn1 and Tuj1 mRNA levels after 50 Hz ELF-EMF exposure (2 mT for 3 days), but the percentages of neurons (Tuj1 ..
  6. Song M, Shirasaki R, Cai C, Ruiz E, Evans S, Lee S, et al. T-Box transcription factor Tbx20 regulates a genetic program for cranial motor neuron cell body migration. Development. 2006;133:4945-55 pubmed
    ..Our study suggests that Tbx20 programs a variety of hindbrain motor neurons for migration, independent of directionality, and in facial neurons is a positive regulator of the non-canonical Wnt signaling pathway. ..
  7. Tsuda H, Takebayashi K, Nakanishi S, Kageyama R. Structure and promoter analysis of Math3 gene, a mouse homolog of Drosophila proneural gene atonal. Neural-specific expression by dual promoter elements. J Biol Chem. 1998;273:6327-33 pubmed
    ..Here, we characterized the genomic organization and promoter activity of mouse ath3 (Math3)...
  8. Seah C, Levy M, Jiang Y, Mokhtarzada S, Higgs D, Gibbons R, et al. Neuronal death resulting from targeted disruption of the Snf2 protein ATRX is mediated by p53. J Neurosci. 2008;28:12570-80 pubmed publisher
    ..Together, these findings show that ATRX deficiency leads to p53-dependent neuronal apoptosis which is responsible for some but not all of the phenotypic consequences of ATRX deficiency in the forebrain. ..
  9. Ding Q, Chen H, Xie X, Libby R, Tian N, Gan L. BARHL2 differentially regulates the development of retinal amacrine and ganglion neurons. J Neurosci. 2009;29:3992-4003 pubmed publisher
    ..Thus, BARHL2 appears to have numerous roles in retinal development, including regulating neuronal subtype specification, differentiation, and survival. ..
  10. Oyama T, Harigaya K, Sasaki N, Okamura Y, Kokubo H, Saga Y, et al. Mastermind-like 1 (MamL1) and mastermind-like 3 (MamL3) are essential for Notch signaling in vivo. Development. 2011;138:5235-46 pubmed publisher
    ..These results indicate that engagement of Mam is essential for Notch signaling, and that the three Mam isoforms have distinct roles in vivo. ..
  11. Ma Q, Chen Z, del Barco Barrantes I, de la Pompa J, Anderson D. neurogenin1 is essential for the determination of neuronal precursors for proximal cranial sensory ganglia. Neuron. 1998;20:469-82 pubmed
    ..ngn1 is required for the activation of a cascade of downstream bHLH factors, including NeuroD, MATH3, and NSCL1. ngn1 is expressed by placodal ectodermal cells and acts prior to neuroblast delamination...
  12. Zou D, Silvius D, Fritzsch B, Xu P. Eya1 and Six1 are essential for early steps of sensory neurogenesis in mammalian cranial placodes. Development. 2004;131:5561-72 pubmed
    ..These analyses define a specific role for both genes in early differentiation and survival of the placodally derived cranial sensory neurons. ..
  13. Eng S, Lanier J, Fedtsova N, Turner E. Coordinated regulation of gene expression by Brn3a in developing sensory ganglia. Development. 2004;131:3859-70 pubmed
  14. Yotsumoto S, Shimada T, Cui C, Nakashima H, Fujiwara H, Ko M. Expression of adrenomedullin, a hypotensive peptide, in the trophoblast giant cells at the embryo implantation site in mouse. Dev Biol. 1998;203:264-75 pubmed
  15. Szabó N, Zhao T, Zhou X, Alvarez Bolado G. The role of Sonic hedgehog of neural origin in thalamic differentiation in the mouse. J Neurosci. 2009;29:2453-66 pubmed publisher
    ..In this way, the individual thalamic nuclei show differential dependence on Shh, Gbx2, or both for their differentiation. Additionally, Gbx2 is required for the survival of thalamic neurons. ..
  16. Medina C, Mazerolle C, Wang Y, Berube N, Coupland S, Gibbons R, et al. Altered visual function and interneuron survival in Atrx knockout mice: inference for the human syndrome. Hum Mol Genet. 2009;18:966-77 pubmed publisher
    ..These results implicate a role for Atrx in interneuron survival and differentiation...
  17. Nakamura K, Itoh K, Yaoi T, Fujiwara Y, Sugimoto T, Fushiki S. Murine neocortical histogenesis is perturbed by prenatal exposure to low doses of Bisphenol A. J Neurosci Res. 2006;84:1197-205 pubmed
    ..5 as compared with those in control mice (n = 10, each). Furthermore, the expression of Math3, Ngn2, Hes1, LICAM, and THRalpha was significantly upregulated at E14.5 in the BPA-treated group...
  18. Mao C, Wang S, Pan P, Klein W. Rewiring the retinal ganglion cell gene regulatory network: Neurod1 promotes retinal ganglion cell fate in the absence of Math5. Development. 2008;135:3379-88 pubmed publisher
    ..We analyzed the retinas of mice in which Math5 was replaced with Neurod1 or Math3, bHLH genes that are expressed in another RPC and are required to establish amacrine cell fate...
  19. Nelson B, Hartman B, Ray C, Hayashi T, Bermingham McDonogh O, Reh T. Acheate-scute like 1 (Ascl1) is required for normal delta-like (Dll) gene expression and notch signaling during retinal development. Dev Dyn. 2009;238:2163-78 pubmed publisher
    ..Thus, these results suggest a molecular mechanism whereby attenuated Notch levels coupled with reduced proneurogenic activity in progenitors leads to increased gliogenesis and decreased neurogenesis in the Ascl1-deficient retina. ..
  20. Menuchin Lasowski Y, Oren Giladi P, Xie Q, Ezra Elia R, Ofri R, Peled Hajaj S, et al. Sip1 regulates the generation of the inner nuclear layer retinal cell lineages in mammals. Development. 2016;143:2829-41 pubmed publisher
  21. Fujitani Y, Fujitani S, Luo H, Qiu F, Burlison J, Long Q, et al. Ptf1a determines horizontal and amacrine cell fates during mouse retinal development. Development. 2006;133:4439-50 pubmed
    ..These data, together with the previous findings on Foxn4, provide a model in which the Foxn4-Ptf1a pathway plays a central role in directing the differentiation of retinal progenitors towards horizontal and amacrine cell fates. ..
  22. Qiu F, Jiang H, Xiang M. A comprehensive negative regulatory program controlled by Brn3b to ensure ganglion cell specification from multipotential retinal precursors. J Neurosci. 2008;28:3392-403 pubmed publisher
    ..Our data suggest that Brn3b specifies the RGC fate from multipotential precursors not only by promoting RGC differentiation but also by suppressing non-RGC differentiation programs as a safeguard mechanism. ..
  23. Hjalt T. Basic helix-loop-helix proteins expressed during early embryonic organogenesis. Int Rev Cytol. 2004;236:251-80 pubmed
  24. Isaka F, Shimizu C, Nakanishi S, Kageyama R. Genetic mapping of four mouse bHLH genes related to Drosophila proneural gene atonal. Genomics. 1996;37:400-2 pubmed
    ..neural disorders, we have determined genetic map positions for four mouse atonal-related genes, Atoh1, Atoh2, Atoh3, and Ndrf, which encode MATH-1, MATH-2, MATH-3, and NDRF, respectively...
  25. Wong R, Wlodarczyk B, Min K, Scott M, Kartiko S, Yu W, et al. Mouse Fkbp8 activity is required to inhibit cell death and establish dorso-ventral patterning in the posterior neural tube. Hum Mol Genet. 2008;17:587-601 pubmed
    ..The mutant Fkbp8 allele is a new experimental model which will be useful in dissecting the pathogenesis of spinal NTDs, and enhance our understanding of the etiology of human NTDs...
  26. Sommer L, Ma Q, Anderson D. neurogenins, a novel family of atonal-related bHLH transcription factors, are putative mammalian neuronal determination genes that reveal progenitor cell heterogeneity in the developing CNS and PNS. Mol Cell Neurosci. 1996;8:221-41 pubmed
    ..The ngn's therefore represent both a family of putative mammalian neuronal determination genes and useful markers of the origins of neuronal diversity. ..
  27. Hatakeyama J, Bessho Y, Katoh K, Ookawara S, Fujioka M, Guillemot F, et al. Hes genes regulate size, shape and histogenesis of the nervous system by control of the timing of neural stem cell differentiation. Development. 2004;131:5539-50 pubmed
  28. Galichet C, Guillemot F, Parras C. Neurogenin 2 has an essential role in development of the dentate gyrus. Development. 2008;135:2031-41 pubmed publisher
    ..These data establish a unique role of Ngn2 in DG neurogenesis during development and raise the possibility that Ngn2 has a similar function in adult neurogenesis. ..
  29. Jadhav A, Mason H, Cepko C. Notch 1 inhibits photoreceptor production in the developing mammalian retina. Development. 2006;133:913-23 pubmed
    ..These cone enriched mutant mice should prove to be a valuable resource for the study of this relatively rare mammalian photoreceptor cell type. ..
  30. Satow T, Bae S, Inoue T, Inoue C, Miyoshi G, Tomita K, et al. The basic helix-loop-helix gene hesr2 promotes gliogenesis in mouse retina. J Neurosci. 2001;21:1265-73 pubmed
    ..In addition, double mutation of the neuronal determination genes Mash1 and Math3, which increases Müller glia at the expense of bipolar cells, upregulated hesr2 expression...
  31. Fode C, Gradwohl G, Morin X, Dierich A, LeMeur M, Goridis C, et al. The bHLH protein NEUROGENIN 2 is a determination factor for epibranchial placode-derived sensory neurons. Neuron. 1998;20:483-94 pubmed
    ..Interestingly, the homeobox gene Phox2a is activated independently of ngn2 in epibranchial placodes, suggesting that neuronal fate and neuronal subtype identity may be specified independently in cranial sensory ganglia. ..
  32. Dai X, Jiang W, Zhang Q, Xu L, Geng P, Zhuang S, et al. Requirement for integrin-linked kinase in neural crest migration and differentiation and outflow tract morphogenesis. BMC Biol. 2013;11:107 pubmed publisher
    ..Changes in these pathways may collectively result in the unique neural crest and outflow tract phenotypes observed in ILK mutants. ..
  33. Akagi T, Inoue T, Miyoshi G, Bessho Y, Takahashi M, Lee J, et al. Requirement of multiple basic helix-loop-helix genes for retinal neuronal subtype specification. J Biol Chem. 2004;279:28492-8 pubmed
    ..In retinas lacking the bHLH genes Ngn2, Math3, and NeuroD, horizontal neurons as well as other neurons such as bipolar cells were severely decreased in number...
  34. Glasco D, Sittaramane V, Bryant W, Fritzsch B, Sawant A, Paudyal A, et al. The mouse Wnt/PCP protein Vangl2 is necessary for migration of facial branchiomotor neurons, and functions independently of Dishevelled. Dev Biol. 2012;369:211-22 pubmed publisher
    ..Interestingly, genetic-interaction experiments suggest that rostral FBM neuron migration, which is normally suppressed, depends upon Dvl function. ..
  35. Daubas P, Tajbakhsh S, Hadchouel J, Primig M, Buckingham M. Myf5 is a novel early axonal marker in the mouse brain and is subjected to post-transcriptional regulation in neurons. Development. 2000;127:319-31 pubmed
    ..This phenomenon may be widespread and it remains to be seen how many other potentially potent regulatory genes, in addition to Myf5, when activated do not accumulate protein at inappropriate sites in the embryo. ..
  36. Masserdotti G, Gillotin S, Sutor B, Drechsel D, Irmler M, Jørgensen H, et al. Transcriptional Mechanisms of Proneural Factors and REST in Regulating Neuronal Reprogramming of Astrocytes. Cell Stem Cell. 2015;17:74-88 pubmed publisher
    ..Within this subset, only NeuroD4 could by itself induce neuronal reprogramming in both mouse and human astrocytes, while co-expression with Insm1 ..
  37. Ma L, Cantrup R, Varrault A, Colak D, Klenin N, Gotz M, et al. Zac1 functions through TGFbetaII to negatively regulate cell number in the developing retina. Neural Dev. 2007;2:11 pubmed
    ..This raises the intriguing possibility that tumorigenicity may also be associated with the loss of feedback inhibition in mature tissues. ..
  38. Cai Z, Feng G, Zhang X. Temporal requirement of the protein tyrosine phosphatase Shp2 in establishing the neuronal fate in early retinal development. J Neurosci. 2010;30:4110-9 pubmed publisher
    ..Together, these results demonstrate that Shp2 mediates FGF-Ras signaling to control retinal progenitor cell fate. ..
  39. Mattar P, Langevin L, Markham K, Klenin N, Shivji S, Zinyk D, et al. Basic helix-loop-helix transcription factors cooperate to specify a cortical projection neuron identity. Mol Cell Biol. 2008;28:1456-69 pubmed
    ..We identify the bHLH gene Math3 as a dorsally restricted Ngn2 transcriptional target and cofactor, which synergizes with Ngn2 to accelerate target ..
  40. Feng L, Xie X, Joshi P, Yang Z, Shibasaki K, Chow R, et al. Requirement for Bhlhb5 in the specification of amacrine and cone bipolar subtypes in mouse retina. Development. 2006;133:4815-25 pubmed
    ..Our results reveal that a bHLH transcription factor cascade is involved in regulating retinal cell differentiation and imply that Bhlhb5 functions downstream of retinogenic factors to specify bipolar and amacrine subtypes. ..
  41. Tomita K, Moriyoshi K, Nakanishi S, Guillemot F, Kageyama R. Mammalian achaete-scute and atonal homologs regulate neuronal versus glial fate determination in the central nervous system. EMBO J. 2000;19:5460-72 pubmed
    ..Here, to address this problem, we generated mice double mutant for the as-c homolog Mash1 and the ato homolog Math3. Whereas in Mash1 or Math3 single mutants neurogenesis is only weakly affected, in the double mutants tectal ..
  42. Schwitzgebel V, Scheel D, Conners J, Kalamaras J, Lee J, Anderson D, et al. Expression of neurogenin3 reveals an islet cell precursor population in the pancreas. Development. 2000;127:3533-42 pubmed
  43. Jones S. An overview of the basic helix-loop-helix proteins. Genome Biol. 2004;5:226 pubmed
    ..In animals, they are important regulators of embryonic development, particularly in neurogenesis, myogenesis, heart development and hematopoiesis. ..
  44. Ohsawa R, Ohtsuka T, Kageyama R. Mash1 and Math3 are required for development of branchiomotor neurons and maintenance of neural progenitors. J Neurosci. 2005;25:5857-65 pubmed
    ..Here, we examined the roles of neural bHLH genes Mash1 and Math3 in the development of trigeminal and facial branchiomotor neurons, which derive from rhombomeres 2-4...
  45. Nakhai H, Sel S, Favor J, Mendoza Torres L, Paulsen F, Duncker G, et al. Ptf1a is essential for the differentiation of GABAergic and glycinergic amacrine cells and horizontal cells in the mouse retina. Development. 2007;134:1151-60 pubmed
    ..We conclude that Ptf1a contributes to the differentiation of horizontal cells and types of amacrine cells during mouse retinogenesis. ..