Abstract
Relative positions of neurons within mature murine pelvic ganglia based on expression of neurotransmitters have been described. However the spatial organization of developing innervation in the murine urogenital tract (UGT) and the gene networks that regulate specification and maturation of neurons within the pelvic ganglia of the lower urinary tract (LUT) are unknown. We used whole-mount immunohistochemistry and histochemical stains to localize neural elements in 15.5 days post coitus (dpc) fetal mice. To identify potential regulatory factors expressed in pelvic ganglia, we surveyed expression patterns for known or probable transcription factors (TF) annotated in the mouse genome by screening a whole-mount in situ hybridization library of fetal UGTs. Of the 155 genes detected in pelvic ganglia, 88 encode TFs based on the presence of predicted DNA-binding domains. Neural crest (NC)-derived progenitors within the LUT were labeled by Sox10, a well-known regulator of NC development. Genes identified were categorized based on patterns of restricted expression in pelvic ganglia, pelvic ganglia and urethral epithelium, or pelvic ganglia and urethral mesenchyme. Gene expression patterns and the distribution of Sox10+, Phox2b+, Hu+, and PGP9.5+ cells within developing ganglia suggest previously unrecognized regional segregation of Sox10+ progenitors and differentiating neurons in early development of pelvic ganglia. Reverse transcription-PCR of pelvic ganglia RNA from fetal and post-natal stages demonstrated that multiple TFs maintain post-natal expression, although Pax3 is extinguished before weaning. Our analysis identifies multiple potential regulatory genes including TFs that may participate in segregation of discrete lineages within pelvic ganglia. The genes identified here are attractive candidate disease genes that may now be further investigated for their roles in malformation syndromes or in LUT dysfunction.
Highlights
Autonomic innervation of the urogenital tract (UGT) controls many fundamental functions including release of hormones from the adrenal, regulation of renal blood flow, peristalsis of urine along the ureters to the bladder, and coordination of urine release from the bladder, as well as sexual arousal
In order to determine whether a similar segregation process might account for the localized expression of Ndrg4 and other transcription factors (TF) in the oval domains we observed in developing pelvic ganglia, we evaluated the distribution of Sox10+ and Phox2b+ cells in lower urinary tract (LUT) tissues of Sox10-H2BVenus, Phox2b-H2BCFP double transgenic fetal mice
It is widely accepted that sacral autonomic ganglia in the LUT derive from progenitors that originate at the Neural crest (NC) and migrate into the region of the cloaca during organogenesis to form the pelvic ganglia
Summary
Autonomic innervation of the urogenital tract (UGT) controls many fundamental functions including release of hormones from the adrenal, regulation of renal blood flow, peristalsis of urine along the ureters to the bladder, and coordination of urine release from the bladder, as well as sexual arousal These critical functions can be disrupted by age, disease, or surgical interventions. Anatomical study of urogenital autonomic ganglia and their accompanying peripheral nerve fibers has been achieved primarily in adult human biopsies and fetal tissues (Jen et al, 1995; Dixon et al, 1998; Yucel et al, 2004) These human studies are challenged by consistency in collection, availability of multiple samples at equivalent developmental stages, and comparison of genetically heterogeneous individuals. They have succeeded in defining the location of nerve fibers in the developing urethral sphincter (Yucel et al, 2004; Karam et al, 2005; Wallner et al, 2009), and mapping neuromuscular junctions as well as generally localizing neuronal and glial elements (Kluck, 1980; Wadhwa and Bijlani, 1983; Elbadawi, 1991; Yucel et al, 2004)
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