Investigating the Transcriptional Regulation of PTF1A and the Function of PRDM13 to Specify Dorsal Spinal Interneurons

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2019-03-28

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Mona, Bishakha

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Transcriptional regulation is a fundamental process required for cell fate specification. During neural development, complex interactions of diverse transcription activators and repressors regulate lineage specific programs. The multitudes of neuronal subtypes generated during development is dependent on spatio-temporally controlled expression of these transcription factors such as bHLH factors, required for cell fate specification. PTF1A is one such factor whose expression is required for specification of the inhibitory fate while silencing the excitatory fate in the neural tube. Previous studies from our lab determined that PTF1A directly activates the inhibitory neuron lineage specific genes to direct neural progenitors towards an inhibitory neuronal fate and initiates a repressive program to suppress the excitatory neuron gene expression program through PRDM13. My thesis work uncovered additional functions of PRDM13 including suppression of ventral neural tube specification genes in the dorsal neural tube through repressing the activity of multiple bHLH transcriptional activators. Additionally, PRDM13 feedback inhibits PTF1A through a Ptf1a auto-regulatory enhancer. Given the indispensable requirement of PTF1A in neural specification, I continued to explore the regulatory network in place for Ptf1a expression. An enhancer with activity specifically in the dorsal neural tube specific was identified for Ptf1a using reporter says in mice and chick. The function the auto-regulatory enhancer and the dorsal neural tube specific enhancer was tested in situ. Mutations in the auto-regulatory enhancer, but not the dorsal neural tube enhancer, resulted in reduced levels of PTF1A, decreased the number of inhibitory neurons generated during dorsal spinal cord development, and exhibit a spontaneous scratching phenotype. The increased sensitivity to itch can be attributed at least in part to loss of BHLHB5;PAX2+ inhibitory neurons, known to play a role in itch. The absence of altered sensitivities in other somatosensory modalities whose information is known to be modulated in dorsal spinal cord circuits suggests itch circuitry is more dependent on PTF1 levels than the other sensory pathways. Together, these findings examine the role of two specific factors PTF1A and PRDM13 in neuronal specification during development.

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