Conditional deletion of Neurog1 in the cerebellum of postnatal mice delays inhibitory interneuron maturation

Abstract

The transcriptional programs that drive the generation of diverse GABAergic neuron populations from their common progenitor pools in the developing cerebellum remain unclear. Neurog1 is a pro-neural basic helix-loop-helix transcription factor expressed in GABAergic progenitor cells in the ventricular zone (VZ) of embryos and subsequently in the presumptive white matter (pWM) tracts of developing postnatal mice. Genetic inducible fate-mapping labels Purkinje cells and all inhibitory interneuron cell types of the cerebellar cortex. As conventional Neurog1 knockout (KO) mice are neonatal lethal, we generated Neurog1 mutant mice to examine the effects of conditional Neurog1 deletion on the postnatal development of the cerebellum. Targeted Neurog1 loss-of-function in the developing cerebellum does not result in significant differences in cerebellar morphology or in the number of GABAergic neurons in the cerebellar cortex of mice at postnatal day 21 (P21). To determine the effects of Neurog1 deletion on GABAergic progenitors, we quantified rates of cell proliferation and cell cycle progression or re-entry in embryonic Neurog1 and postnatal Neurog1 mutants. The data revealed no significant effect of Neurog1 loss-of-function on embryonic day 12.5 (E12.5) VZ progenitors or on P5 and P6 progenitors in the pWM at P7. However, 4-5 day pulse-labeling of P5 and P6 progenitors revealed reductions in inhibitory interneuron dispersal from the pWM to the cerebellar cortex in P10 conditional Neurog1 KO mice. Thus, our conditional Neurog1 KO approach reveals a requirement for Neurog1 activity in inhibitory interneuron cell dispersal from pWM tracts in the developing cerebellum of postnatal mice.

Transcriptome clarifies mechanisms of lesion genesis versus progression in models of Ccm3 cerebral cavernous malformations

“…In the acute in vivo NVUs model, four genes including Lbx1 , Pax2 , Pax3 , Neurog1 were identified among the top-20 DEGs, and were related to neural development [30, 42, 43]. Barhl1 also belonged to the top-20 DEGs and genetically engineered Barhl1 −/− mice model develop medulloblastoma-phenotype [46].…”

Cell–Cell Contact Mediates Gene Expression and Fate Choice of Human Neural Stem/Progenitor Cells

“…ASCL1 is a pioneer transcription factor that is necessary to promote NPC proliferation, as well as the specification of neurogenic cell fates through increased chromatin accessibility and de novo gene expression [ 59 , 60 ]. NEUROG1/2 expression was also increased in high density cultures, which are proneuronal transcription factors that can initiate neuronal differentiation [ 61 , 62 , 63 ]. Not only can it promote the differentiation capacity into neurons, but NEUROG1 signaling simultaneously inhibits gliogenesis by sequestering the gliogenic-Smad1/CBP/p300 activating complex away from STAT-promoter sites, and towards neurogenic transcriptional activation.…”

Regulation of early cerebellar development

“…Despite the fact that Ascl1 is highly expressed in the ventricular zone during the specification of Purkinje cells, the loss of this factor has little effect on their specification, albeit the generation of cerebellar inhibitory interneurons and glial cells is largely affected [140–142]. Similarly, the ablation of Neurog1 from ventricular zone progenitors does not significantly alter the development of Purkinje cells, but does slightly impair the development of cerebellar inhibitory neurons, with a mild reduction in the numbers of interneurons generated in early postnatal life [143]. Neurog2 actively regulates the proliferation of ventricular zone progenitor cells that generate Purkinje cells [144].…”