Examining the Role of PRDM13 in Dorsal Interneuron Specification

PTF1A is a transcription factor transiently expressed as neural progenitor cells become post-mitotic and begin to express neuronal specific genes. PTF1A specifies these cells to become GABAergic (inhibitory) neurons while suppressing the glutamatergic (excitatory) program. A fundamental principle in bipotential fate decisions is the necessity to repress gene programs in the alternative fate. Our lab identified PRDM13, a zinc finger transcription factor and direct downstream target of PTF1A that may serve this function in the inhibitory/excitatory neuron fate choice. Overexpression of PRDM13 in chick neural tube shows it represses markers of the excitatory neuronal lineage. To explore PRDM13 function in vivo and expand these findings to regions outside the neural tube, a Prdm13GFP_KI and Prdm13ΔZF mutant mouse strains was generated and are null for PRDM13 expression. These mice die neonatally and at E10.5 show an increase in the dorsal neural tube excitatory neuron population at the expense of the inhibitory neurons. These phenotypes recapitulate that seen in Ptf1a null mice. These models have revealed additional insights into the function of PRDM13 in the developing spinal cord. First, PRDM13 negatively regulates Ptf1a providing a mechanism for downregulating PTF1A as development progresses. Second, in contrast to the phenotype seen with Ptf1a mutants, late stage mutant embryos show only a partial loss of the inhibitory interneuron population, possibly due to the higher levels of PTF1A in these mutants. Finally, ChIP-Seq and RNA-Seq analysis of heterozygote vs homozygote Prdm13 mutants revealed a novel function of PRDM13 to keep neuronal subtype specification genes for the ventral neural tube suppressed in the dorsal region. These mouse models has placed PRDM13 in a pivotal role in the specification of neuronal subtypes in the spinal cord, a function that will likely extend to the retina and cerebellum where PRDM13 is also present.