The potential role of Rac signalling and the planar cell polarity pathway in wiring of the enteric nervous system.
Doctoral thesis, UCL (University College London).
The functional development of the enteric nervous system (ENS) requires newly generated neurons and their progenitors to migrate to their appropriate sites, extend neurites, guide axons and dendrites to suitable locations and establish synaptic connections with the appropriate targets. Very little is known about the molecular mechanism underlying these processes. Recent studies have suggested a potential role of Rho GTPases as intracellular regulators of several ENS developmental processes. However, the relative participation of specific members of the family in migration, neurogenesis and axonal guidance of enteric progenitors has not been addressed yet. Here, we investigate the in vivo role and genetic interaction of two members of the Rho-GTPase family, Rac1 and Rac3 in enteric neurogenesis. Taking advantage of the Cre/loxP recombination system and a Rac1 conditional inactivation mouse strain (Rac1flox/flox), we generated a Sox10Cre; Rac1flox/flox;R26ReYFP mouse line, where Rac1 gene is specifically ablated in the neural crest population which is also labeled by the expression of Yellow Fluorescent Protein. Secondly, we generated double Rac1;Rac3 mutant animals by crossing the Sox10Cre;Rac1flox;R26ReYFP mouse line to a constitutive Rac3 KO strain (Rac3-/-). In vivo and in vitro studies on Rac-deficient enteric neural crest cells and neurons showed distinctive roles for Rac1 and Rac3 in migration of enteric neural crest cells (ENCCs), in development of enteric neurons and in control of cell polarity within the developing ENS. In addition, we also undertook a candidate gene approach to investigate the involvement of Wnt-signaling genes in enteric axon guidance and circuit formation. We found that two of the core components of the Planar Cell Polarity pathway, the Wnt receptor Frizzled 3 (Fzd3) and the Cadherin EGF LAG seven-pass G-type receptor 3 (Celsr3) are expressed specifically in ENCCs during embryonic development. Here we show, by using a combination of in vivo approaches that in mice deficient in either protein, enteric neurons had characteristic defects in neuronal tract formation and in patterning of individual axonal projections evident from early stages of ENS development. Furthermore, preliminary data show that these specific defects in ENS wiring might be the cause of impaired intestinal function and, therefore, provide the basis for understanding the aetiopathology of several idiopathic enteric neuropathies in humans.
|Title:||The potential role of Rac signalling and the planar cell polarity pathway in wiring of the enteric nervous system|
|Open access status:||An open access version is available from UCL Discovery|
|UCL classification:||UCL > School of Life and Medical Sciences > Faculty of Life Sciences > Biosciences (Division of) > Cell and Developmental Biology|
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