Regulation Of Axon Guidance Receptor Expression And Activity During Neuronal Morphogenesis

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Doctor of Philosophy (PhD)
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Cell & Molecular Biology
Axon guidance
Homeodomain proteins
Motor neurons
Developmental Biology
Neuroscience and Neurobiology
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Receptors expressed on the surface of neurons during development direct cell migration, axon guidance, dendrite morphogenesis, and synapse formation by responding to cues in the neuron’s environment. The expression levels and the activity of cell surface receptors must be tightly controlled for a neuron to acquire its unique identity. Transcriptional mechanisms are essential in this process, and many studies have identified requirements for specific transcription factors during the different steps of neural circuit assembly. However, the downstream effectors by which most of these factors control morphology and connectivity remain unknown. In Chapter 1, I highlight recent work that elucidated functional relationships between transcription factors and the cellular effectors through which they regulate neural morphogenesis and synaptogenesis in multiple model systems. In Chapters 2 and 3, I present data demonstrating that the homeodomain transcription factors Hb9 and Islet control motor axon guidance in Drosophila embryos through distinct effectors: Hb9 regulates the (Roundabout) 2 receptor in a subset of motor neurons, while Islet acts in the same cells to regulate the Frazzled/DCC receptor. Genetic rescue experiments indicate that these relationships are functionally important for the guidance of motor axons to their muscle targets. In addition, Islet regulates motor neuron dendrite targeting in the central nervous system (CNS) through Frazzled, demonstrating how an individual transcription factor can control multiple aspects of neuronal connectivity through the same effector. In Chapter 4, I characterize a non-canonical function for the Robo2 receptor during midline crossing, and present data suggesting that this activity requires Robo2 to be expressed in midline cells, providing an example of how mechanisms that regulate guidance receptor gene expression are key to regulating receptor function and nervous system formation. In Chapter 5, I explore the implications of these findings, and propose future directions of research to build upon them.

Greg J. Bashaw
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