Abstract
BackgroundThe high mobility group (HMG) family transcription factor Sox9 is critical for induction and maintenance of neural stem cell pool in the central nervous system (CNS). In the spinal cord and retina, Sox9 is also the master regulator that defines glial fate choice by mediating the neurogenic-to-gliogenic fate switch. On the other hand, the genetic repertoire governing the maintenance and fate decision of neural progenitor pool in the cerebellum has remained elusive.ResultsBy employing the Cre/loxP strategy, we specifically inactivated Sox9 in the mouse cerebellum. Unexpectedly, the self-renewal capacity and multipotency of neural progenitors at the cerebellar ventricular zone (VZ) were not perturbed upon Sox9 ablation. Instead, the mutants exhibited an increased number of VZ-derived neurons including Purkinje cells and GABAergic interneurons. Simultaneously, we observed continuous neurogenesis from Sox9-null VZ at late gestation, when normally neurogenesis ceases to occur and gives way for gliogenesis. Surprisingly, glial cell specification was not affected upon Sox9 ablation.ConclusionOur findings suggest Sox9 may mediate the neurogenic-to-gliogenic fate switch in mouse cerebellum by modulating the termination of neurogenesis, and therefore indicate a functional discrepancy of Sox9 between the development of cerebellum and other major neural tissues.
Highlights
The high mobility group (HMG) family transcription factor Sox9 is critical for induction and maintenance of neural stem cell pool in the central nervous system (CNS)
Since the onset of cerebellar neurogenesis at embryonic day 10.5 (E10.5), GABAergic neurons including Purkinje cells and deep cerebellar nuclei neurons are produced from the ventricular zone (VZ) by asymmetric, neurogenic division of radial glial cells and become terminally differentiated [5], whilst neuronal progenitors committed to inhibitory interneurons delaminate from the VZ and continue to proliferate within the prospective white matter (PWM) until after birth [6,7]
By E18.5, Sox9 expression was detected in the nascent Purkinje cell layer (PCL) where they co-localized with Excitatory amino acid transporter 1 (EAAT1), a marker for the differentiated astrocytic lineage at late embryonic stages
Summary
The high mobility group (HMG) family transcription factor Sox is critical for induction and maintenance of neural stem cell pool in the central nervous system (CNS). Since the onset of cerebellar neurogenesis at embryonic day 10.5 (E10.5), GABAergic neurons including Purkinje cells and deep cerebellar nuclei neurons are produced from the VZ by asymmetric, neurogenic division of radial glial cells and become terminally differentiated [5], whilst neuronal progenitors committed to inhibitory interneurons delaminate from the VZ and continue to proliferate within the prospective white matter (PWM) until after birth [6,7]. During these initial progressive waves of neurogenesis the VZ generates very few, if any, glial populations. This sequential production of neurons and glia from the VZ neuroepithelium is not a phenomenon unique to the cerebellum, but is rather a process fundamental to the entire developing CNS and is conserved
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