Takako Makita, Ph.D. - US grants

[unreadable] DESCRIPTION (provided by applicant): [unreadable] [unreadable] A key process in developmental neurobiology is the manner by which axons projecting from newly born neurons choose paths to reach and innervate target organs. This proposal addresses the role of endothelin signaling as a critical mechanism that controls the projection of sympathetic axons from the superior cervical ganglia (SCG). New observations described in this proposal lead to a model in which vascular smooth muscle-derived endothelins provide guidance cues for sympathetic axons from the SCG to take a specific vascular trajectory, along the external carotid artery. A subset of SCG neurons express the type A endothelin receptor (ETA), which is essential for SCG axons to choose between distinct trajectories and to innervate their appropriate target tissues. In this application, I propose experiments to address and extend a model in which endothelin signaling, emanating from smooth muscle of the external carotid arteries, is a required guidance cue for SCG axons. [unreadable] Specific Aim1: To define the genetic requirements for endothelin signaling components in SCG axon guidance. This aim addresses the mechanism of endothelin ligand production by smooth muscle specifically of the external carotid arteries. [unreadable] Specific Aim 2: To define the tissue-specific functions of endothelin signaling components in SCG axon guidance. This aim addresses the extent to which ETA is intrinsically required by SCG neurons to respond endothelins in order to project along the external carotid arteries. [unreadable] Specific Aim3: To define the molecular basis of defective SCG outgrowth in Hoxa3 mutant mice. In this aim, I will evaluate how expression of endothelin signaling components is perturbed in Hoxa3 mutant mice, which have a comparable SCG outgrowth deficiency as seen in ETA-deficient embryos. [unreadable] Public health relevance: This research addresses the molecular basis of nerve-blood vessel congruency and the establishment of proper neural circuitry during development, both of which are relevant to the treatment for congenital defects in neural innervations, and for regeneration of neural circuitry following neurological diesease or injury. The principles learned will also apply to organ transplantation studies to achieve reinnervation of amputated axons to transplanted organs. [unreadable] [unreadable] [unreadable]

DESCRIPTION (provided by applicant): During embryonic development, the heart becomes innervated by sympathetic nerves, which control heart rate and contractility. Sympathetic nerve extend along blood vessels to reach their targets, in what is called neurovascular congruency, but virtually nothing is known of how these axons are instructed to reach the heart in order to establish a precise circuitry. New observations described in this proposal lead to a model in which endothelin signaling from specific vascular components is a critical guidance mechanism for sympathetic axons to take appropriate routes in order to reach the heart. In this application, using both in vivo and in vitro assays, I propose experiments to address the spatial and functional role of specific components of endothelin signaling in cardiac axon guidance. I approach this strategy within a developmental context that coordinates neuronal outgrowth with cardiovascular cell lineage and morphogenesis.

DESCRIPTION (provided by applicant): Hirschsprung's disease is a congenital gut motility disorder caused by the failure of neural crest migration to the gastrointestinal tract. Neural cres is responsible for formation of the enteric nervous system, and their absence results in an aganglionic segment in the terminal bowel, which results in a failure to promote peristaltic contraction. New observations described in this proposal lead to a model in which placode cells also migrate and colonize the gut and selectively give rise to the intrinsic sensory neurons of the enteric ganglia, whereas neural crest cells contribute to non-sensory population (motor neurons, interneurons, and glia). In this application, I propose experiments to define the fate of enteric placode in the enteric nervous system, and to address how endothelin and Ret signaling control both neural crest and placode cell migration and colonization of the gut. Furthermore, I propose to address a model in which the intrinsic airway ganglia of the pulmonary plexus are also derived from both placode and neural crest, which will provide new insight into pathogenesis of the Hirschsprung's disease associated syndrome, Congenital central hypoventilation syndrome (CCHS).