Abstract
The interface between our mind and the internal and external environments is the peripheral nervous system. A range of different sensory neuron subtypes detects cold, heat, pain, touch, and other stimuli. Specialized receptor molecules defining the sensory modality of the cell, specific target innervation, and central connectivity characterize the neuronal subtypes. Neural crest cells (NCCs) are a transient population of pluripotent cells in the embryo that arise between the neural ectoderm and the ectoderm, go through epithelial to mesenchymal transition, migrate through the embryo and give rise to a wide range of tissues and cell types. Among NCC derivatives are the neurons and glia of the peripheral nervous system, with sensory neurons populating the dorsal root ganglia (DRG) and sympathetic neurons populating the sympathetic chain; other cell types are melanocytes, and jawbone tissue. During migration, an individual NCC gradually goes through a series of fate restrictions, driven by extrinsic cues and intrinsic properties. How and when is the diversity of neural crest derived cells and more specifically sensory neuronal subtypes created?
This thesis explores the role of transcription factors in sensory neuron specification. We describe the transcription factor Foxs1 as an early sensory neuronal marker and use it to describe molecularly distinct waves of neurogenesis in the trunk DRG. Our work shows that Runx1 directs the establishment of the TrkA+ nociceptive subclass of neurons. We describe context-dependent downstream effects of Runx1 overexpression, as well as loss of function effects. These effects include direct transactivation of TrkA, incompatibility with multipotency marker Sox10, increased axonal growth, and branching, and effects on survival prior to the period of programmed cell death. We report the results of an unbiased screen for downstream targets of Runx transcriptional activities in sensory neuron development and apoptosis.
In conclusion, this thesis describes crucial aspects of sensory neuron development and subtype specification, focusing on the role of transcription factors.
