A non-canonical role for the proneural gene Neurog1 as a negative regulator of neocortical neurogenesis
journal contributionposted on 2020-08-05, 16:34 authored by Sisu Han, Daniel J Dennis, Anjali Balakrishnan, Rajiv Dixit, Olivier Britz, Dawn Zinyk, Yacine Touahri, Thomas Olender, Marjorie Brand, François Guillemot, Deborah Kurrasch, Carol Schuurmans
Neural progenitors undergo temporal identity transitions to sequentially generate the neuronal and glial cells that make up the mature brain. Proneural genes have well-characterised roles in promoting neural cell differentiation and subtype specification, but they also regulate the timing of identity transitions through poorly understood mechanisms. Here, we investigated how the highly related proneural genes Neurog1 and Neurog2 interact to control the timing of neocortical neurogenesis. We found that Neurog1 acts in an atypical fashion as it is required to suppress rather than promote neuronal differentiation in early corticogenesis. In Neurog1-/- neocortices, early born neurons differentiate in excess, whereas, in vitro, Neurog1-/- progenitors have a decreased propensity to proliferate and form neurospheres. Instead, Neurog1-/- progenitors preferentially generate neurons, a phenotype restricted to the Neurog2+ progenitor pool. Mechanistically, Neurog1 and Neurog2 heterodimerise, and while Neurog1 and Neurog2 individually promote neurogenesis, misexpression together blocks this effect. Finally, Neurog1 is also required to induce the expression of neurogenic factors (Dll1 and Hes5) and to repress the expression of neuronal differentiation genes (Fezf2 and Neurod6). Neurog1 thus employs different mechanisms to temper the pace of early neocortical neurogenesis.
NeocortexNeurogenesisNeurogeninsProneural genesbHLH transcription factorsAnimalsBasic Helix-Loop-Helix Transcription FactorsCell DifferentiationCell ProliferationCell Self RenewalEmbryo, MammalianGene Expression Regulation, DevelopmentalMice, TransgenicNerve Tissue ProteinsNeural Stem CellsNeurogliaNeuronsProtein BindingTime FactorsTranscription, GeneticGuillemot FC00108906 Biological Sciences11 Medical and Health Sciences