Transcriptional manipulation of post-stroke axonal sprouting: A study of developmental transcription factors Ctip2 and Hhex

The ability of the nervous system to repair itself following injury is a remarkable phenomenon, but central nervous system endogenous repair mechanisms are incomplete. Cortical ischemic stroke produces a limited process of neural repair, characterized by axonal sprouting and reorganization in the surviving tissue adjacent to the infarct. Changes in gene expression patterns have been observed in this peri-infarct region, in populations of neurons that specifically sprout new axons following stroke, and in neurons that have received delivery of growth factors following stroke, providing transcriptomic profiles of neuronal growth states post-stroke. Within these transcriptomic data sets are a number of differentially regulated transcription factors that have been implicated in brain development. Developmental transcription factors present an intriguing target for study due to their inherent ability to act as master regulators of genes responsible for neuronal growth. This thesis investigates a selection of these differentially regulated transcription factors for their ability to regulate axonal sprouting and functional recovery following stroke. Genes were screened for their ability to promote axonal growth in primary cortical neurons. From these studies, Hhex and Ctip2 emerged as candidates for further exploration. Overexpression of these genes following stroke revealed an ability of both Hhex and Ctip2 to promote long-distance axonal sprouting, but only Hhex to promote axonal sprouting in the peri-infarct region. Overexpression of Hhex or Ctip2 showed an ability to promote recovery of gait function following stroke to the forelimb motor cortex, but only overexpression of Hhex was associated with recovery of forelimb reach movements and fine motor manipulation. Transcriptional profiling of neurons that have Ctip2 or Hhex overexpressed following stroke revealed that these transcription factors are driving different molecular pathways to achieve axonal growth and functional recovery. Ultimately, these studies implicate a role for these transcription factors in axonal growth in the adult brain and provide further evidence for unique intrinsic growth programs in neural repair processes