title: Basic helix-loop-helix transcription factors cooperate to specify a cortical projection neuron identity.
abstract: Several transcription factors are essential determinants of a cortical projection neuron identity, but their mode of action (instructive versus permissive) and downstream genetic cascades remain poorly defined. Here, we demonstrate that the proneural basic helix-loop-helix (bHLH) gene Ngn2 instructs a partial cortical identity when misexpressed in ventral telencephalic progenitors, inducing ectopic marker expression in a defined temporal sequence, including early (24 h; Nscl2), intermediate (48 h; BhlhB5), and late (72 h; NeuroD, NeuroD2, Math2, and Tbr1) target genes. Strikingly, cortical gene expression was much more rapidly induced by Ngn2 in the dorsal telencephalon (within 12 to 24 h). We identify the bHLH gene Math3 as a dorsally restricted Ngn2 transcriptional target and cofactor, which synergizes with Ngn2 to accelerate target gene transcription in the cortex. Using a novel in vivo luciferase assay, we show that Ngn2 generates only approximately 60% of the transcriptional drive in ventral versus dorsal telencephalic domains, an activity that is augmented by Math3, providing a mechanistic basis for regional differences in Ngn2 function. Cortical bHLH genes thus cooperate to control transcriptional strength, thereby temporally coordinating downstream gene expression.
authors.affiliation: Institute of Maternal and Child Health, Hotchkiss Brain Institute, University of Calgary, 2277 HSC, 3330 Hospital Dr. NW, Calgary, Alberta, Canada.
authors.forename: Pierre
authors.initials: P
authors.lastname: Mattar
authors.forename: Lisa Marie
authors.initials: LM
authors.lastname: Langevin
authors.forename: Kathryn
authors.initials: K
authors.lastname: Markham
authors.forename: Natalia
authors.initials: N
authors.lastname: Klenin
authors.forename: Salma
authors.initials: S
authors.lastname: Shivji
authors.forename: Dawn
authors.initials: D
authors.lastname: Zinyk
authors.forename: Carol
authors.initials: C
authors.lastname: Schuurmans
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics; D015415:Biomarkers / Q000378:metabolism; D002232:Carbocyanines / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics; D019070:Cell Lineage / Q000235:genetics; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology*; D018274:Electroporation; D004622:Embryo, Mammalian; D005456:Fluorescent Dyes / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D049452:Green Fluorescent Proteins / Q000378:metabolism; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D008156:Luciferases / Q000378:metabolism; D051379:Mice; D008815:Mice, Inbred Strains; D008817:Mice, Mutant Strains; D008959:Models, Neurological; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics; D009474:Neurons / Q000166:cytology*; D010957:Plasmids; D013687:Telencephalon / Q000166:cytology / Q000196:embryology; D013997:Time Factors; D014157:Transcription Factors / Q000235:genetics*
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D015415:Biomarkers; D002232:Carbocyanines; D005456:Fluorescent Dyes; D049452:Green Fluorescent Proteins; D008156:Luciferases; D009419:Nerve Tissue Proteins; D014157:Transcription Factors; C104516:Neurod4 protein, mouse; C102938:Neurog2 protein, mouse; C407737:Neurog3 protein, mouse; C089187:cyanine dye 3