Prdm13, a Direct Downstream Target of Ptf1a, Regulates the Balance of Gabaergic Neurons versus Glutamatergic Neurons in the Dorsal Spinal Cord




Chang, Joshua Chia-Hsi

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A fundamental question in neural development addresses the molecular mechanism for balancing the equilibrium of inhibitory versus excitatory (E/I balance) neurons. The combination of basic helix-loop-helix (bHLH) and homeodomain (HD) transcription factors is essential to generate the E/I balance required for correct functioning of neural networks. During dorsal spinal cord development, the bHLH factor Ascl1 is expressed in progenitors to dI3, dI4, and dI5 (dorsal interneurons 3-5) and is required for the glutamatergic neuronal fate. In contrast, another bHLH factor Ptf1a, is restricted in progenitors to dI4 and is required to specify the GABAergic neuronal fate. Since progenitors to dI4 express both Ascl1 and Ptf1a, some mechanism must exist to repress Ascl1 specification activities in these cells. Given that Ptf1a acts as a transcriptional activator, I hypothesized that Ptf1a induces a transcriptional repressor as one of its downstream targets to mediate the suppression of glutamatergic lineage genes. A chromatin-remodeling transcription factor, Prdm13 (PRDI-BF1 and RIZ homology domain containing 13), was identified as a direct target of Ptf1a. The expression pattern of Prdm13 reflects that of Ptf1a in the spinal cord, cerebellum, diencephalon, and retina, and Ptf1a is the primary factor required for Prdm13 expression. Furthermore, I demonstrate that Prdm13 functions as a transcriptional repressor to actively suppress the excitatory cell fate by binding to specific cis-elements near the glutamatergic lineage regulatory genes, Tlx1 and Tlx3, to silence their expression. Prdm13 acts through multiple protein/DNA complexes, including a novel complex with Ascl1, to repress Ascl1 activation of Tlx3. Prdm13 is also sufficient to induce Pax2 and the GABAergic phenotype. This aspect of Prdm13 function is likely indirect through repression of Tlx1/3 since it is known that Tlx1/3 normally blocks the HD factor Lbx1 that is also involved in GABAergic neuronal specification. Taken together, Prdm13 is a direct target of Ptf1a and is required to suppress the glutamatergic neuronal gene program in GABAergic neurons in the dorsal spinal cord. Therefore, Prdm13 is a novel component of a highly coordinated transcriptional network that provides a missing link in a cell fate decision required for somatosensory processing in the spinal cord.

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