Neural Crest Contributions to the Lower Urinary Tract

Vanderbilt University, Nashville TN

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Abstract

Innervation of the bladder and urethra determines appropriate bladder contractility and regulates urinary continence. Anatomical and immunohistochemical studies of pelvic innervation have identified neural components and some of the neurotransmitter subtypes within pelvic ganglia that are present in late fetal and postnatal development. However, a comprehensive fate map of cell types in the lower urinary tract (LUT) is lacking. Peripheral ganglia including pelvic autonomic ganglia derive from neural crest (NC) progenitors. Identification of NC lineages and genes that control their differentiation within the bladder and urethra are highly significant for understanding the etiology and potential treatments for neurogenic bladder and urinary incontinence. Spina bifida and spinal dysraphism are the most common causes of pediatric neurogenic bladder dysfunction. The association between neural tube defects and bladder dysfunction as well as the NC origin of sympathetic and parasympathetic inputs that innervate the bladder implies that NC derivatives are essential participants in normal bladder development. In vitro neural crest stem cels are capable of generating neurons, glia and myofibroblasts. It remains to be seen whether only pelvic autonomic neurons and glia are NC- derived or if neural crest stem cells also contribute additional lineages to the LUT in vivo. Alternatviely, it is possible that NC-derived progenitors exert inductive effects on developing muscle in the LUT analogous to inductive events in cardiac development. We will test the hypothesis that multiple lineages within the bladder are NC-derived and required for normal bladder development through analysis of engineered mouse models. Aim 1 will derive a comprehensive fate map of NC-derived lineages in the LUT. Aim 2 will define mechanisms of altered NC development in a mouse spina bifida model with features of neurogenic bladder. Aim 3 will target temporal and tissue specific ablation of Pax3 to establish lineage requirements for this gene in directing NC progenitors as they populate the bladder. Our analysis will pioneer exploration of NC lineages pathways in the bladder and define mechanisms of altered NC development in spina bifida mouse models that are relevant for understanding the etiology of neurogenic bladder in patients.