PRDM13 is required for specification of PAX2 lineage inhibitory neurons in the developing cerebellum

Abstract

Shared genetic developmental programs in which specific transcription factors affect similar cell fate decisions in distinct tissues are common. In the developing dorsal neural tube and cerebellum, PTF1A is essential for specification of GABAergic inhibitory neurons and suppression of alternative glutamatergic excitatory neuronal fates. Previous studies in the mouse dorsal neural tube identified the transcriptional repressor PRDM13 as a transcriptional target of PTF1A that functions to suppress the alternate cell fates to ensure precision in neuronal cell identity. The presence of PRDM13 in PTF1A + cerebellar progenitors suggests a similar role for PRDM13 in cerebellar neuronal specification. Cerebellar agenesis in humans with missense mutations in PRDM13, and perturbations in cerebellar development in Prdm13 mutant mice and zebrafish, confirm PRDM13 requirement in this tissue. Here we add to these findings showing additional mutant alleles in mouse Prdm13 phenocopy the perturbation in cerebellar cell fates seen with the absence of PTF1A, including loss of PAX2+ interneuron and Purkinje cell inhibitory neuronal lineages, increases in TLX3+ excitatory neuronal lineages, increased apoptosis, and reduced cerebellar size. Additional defects are seen in the placement of TBR1+ cerebellar cells. Thus, using Prdm13 mutant mice, we support conclusions that PRDM13 functions to specify balanced numbers of inhibitory and excitatory neuronal progenitors in the developing cerebellum.