The balance between inhibitory and excitatory neurons is established early in development in a process dominated by the interplay between the transcriptional activator PTF1A and the repressor PRDM13 in multiple regions of the nervous system. Initial cell fate decisions that ultimately give rise to inhibitory neurons in the dorsal spinal cord, cerebellum, and retina depend on the early activity of these fate-specifying transcription factors (TFs). PTF1A, like other early- acting basic helix-loop-helix (bHLH) factors, acts as a `master regulator' by triggering downstream genetic cascades. Such TFs have profound effects by restricting progenitor developmental potential long before the appearance of mature neurons. In the absence of PTF1A, neural progenitors fail to generate inhibitory neurons and aberrantly assume an excitatory neuronal fate. Thus, the spatial and temporal control of PTF1A expression controls the formation of the inhibitory/excitatory balance in multiple neuronal circuits.
In Aim 1 we will examine the in vivo requirement for a dorsal neural tube specific enhancer for Ptf1a at the molecular, cellular, and behavioral levels. PRDM13, a transcriptional repressor and a direct target of PTF1A, ensures correct specification of dorsal spinal cord inhibitory neurons by repressing genes essential for specifying the alternative excitatory neuronal fates. Because PRDM factors can have methyltransferase activity and/or can recruit other chromatin modifying enzymes, and PRDM13 may bind to bHLH TFs, PRDM13 may provide a molecular link between these factors and accompanying changes in the epigenetic landscape during neuronal subtype- specification. Indeed, PRDM13 binds many similar genomic sites as PTF1A and another bHLH factor ASCL1.
In Aims 2 and 3, we will probe PRDM13 functions in the developing nervous system, and test the hypothesis that PRDM13 is recruited to bHLH bound sites to facilitate repressive chromatin modifications to repress transcription through these sites.
Alterations in the balance of inhibitory and excitatory neurons are thought to underlie diverse neurological disorders including those involving spinal cord such as pain, itch, touch, and sense of limb position. PTF1A and its downstream target PRDM13 are essential regulators of this balance in multiple regions of the nervous system including spinal cord, cerebellum, and retina. Regulatory mechanisms identified here may influence strategies for manipulating the fate of stem cells for regenerative purposes, and are likely to provide fundamental principles of gene regulation common to developing systems.
| Goodson, Noah B; Nahreini, Jhenya; Randazzo, Grace et al. (2018) Prdm13 is required for Ebf3+ amacrine cell formation in the retina. Dev Biol 434:149-163 |
| Mona, Bishakha; Uruena, Ana; Kollipara, Rahul K et al. (2017) Repression by PRDM13 is critical for generating precision in neuronal identity. Elife 6: |
