Our goal is to reveal developmental and genetic mechanisms that control formation of cell types from the neural crest (NC) in the lower urinary tract (LUT). NC progenitor cells form pelvic autonomic ganglia and peripheral glia along nerve fibers that innervate all aspects of this organ system. Appropriate innervation of the bladder and urethra are required for normal bladder contractility and urinary continence. Failure to regulate normal urine pressures within the bladder, as occurs in neurogenic bladder, predisposes to kidney failure when high pressures damage glomeruli. In children, Spina bifida (SB) and spinal dysraphism are the most common causes of neurogenic bladder dysfunction, with patients exhibiting deficits of bladder wall nerves and muscle. 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 cells are capable of generating neurons, glia and myofibroblasts. However, a fate map of the LUT with cellular resolution that relates mature NC-derived cell types to structures within this organ system does not yet exist. Thus it remains to be seen whether only pelvic autonomic neurons and glia are NC-derived or if neural crest stem cells also contribute other essential cell types to the LUT. Alternatively, it is possible that NC-derived progenitors exert inductive effects on developing muscle in the LUT analogous to inductive mechanisms in cardiac and thymus development. We will test the hypothesis that multiple lineages within the bladder are NC- derived and are 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 SB model that mimics LUT deficiencies seen in SB patients.
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 in the bladder and identify altered developmental processes in a mouse model of SB that are relevant for understanding the etiology of bladder disease in SB patients.
Normal development of the lower urinary tract including the bladder and urethra during fetal life is critical for elimination of urine after birth. Defects in etal development that disrupt formation of nerves in the lower urinary tract, like spina bifida, can lea to kidney failure later when the bladder is unable to contain urine at normal pressures. This proposal will use mouse models to investigate developmental mechanisms that normally control formation of nerves in the lower urinary tract and determine how defects that cause spina bifida produce bladder abnormalities.
|Georgas, Kylie M; Armstrong, Jane; Keast, Janet R et al. (2015) An illustrated anatomical ontology of the developing mouse lower urogenital tract. Development 142:1893-908|