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

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^Neoknockout (KO) mice are neonatal lethal, we generated Neurog1^loxPmutant 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^Neoand postnatal Neurog1^loxPmutants. 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^loxP/loxPKO 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.