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|Title: ||Mechanisms of epithelial branching, nephrogenesis, and the role of the Rho-GTPase family in kidney development|
|Authors: ||Lindström, Nils Olof|
|Supervisor(s): ||Davies, Jamie|
|Issue Date: ||2009|
|Publisher: ||The University of Edinburgh|
|Abstract: ||The metanephric kidney consists of two types of epithelia; the Wolffian duct-derived
ureteric bud and the nephrogenic components that originate from mesenchymal-toepithelial
transitions in the metanephric mesenchyme. The ureteric bud forms when
inductive signals from the metanephric mesenchyme stimulates the evagination of an
epithelial tube from the Wolffian duct into the mesenchyme. Reciprocal signalling
between the ureteric bud and the metanephric mesenchyme regulates the branching of
the ureteric bud and the induction of nephron formation. Inductive and inhibitory
signalling of ureteric bud growth and branching has been shown by several protein
families, however, the mechanical aspects of ureteric bud branching and nephrogenesis
are largely unknown.
I investigated the roles of Rac1-GTPase and Rho-kinase during kidney development.
These proteins are important regulators of the cytoskeleton where Rac1 is a promoter of
actin filament polymerisation and Rho-kinase directly stimulates the formation and
contraction of actin-myosin stress fibres. Using a cell-permeable inhibitor, Rac1 was
inhibited with no effects on nephron formation or subsequent segmentation and
patterning. Inhibition of active Rac1 significantly reduced the level of ureteric bud
branching and also resulted in lower proliferation rates.
Rho-kinase was similarly targeted using two inhibitors. Rho-kinase inhibition had
important effects on nephron formation and nephron maturation. Inhibition of Rhokinase
resulted in decreased levels of nephron formation and severely morphologically
abnormal nephrons. The formation of apical-basal polarity was disturbed as was the
development of the visceral and parietal epithelia; precursors of the renal corpuscle.
Inhibition of Rho-kinase led to abnormal formation of the proximal-distal axis and
abnormal segmentation of the nephron. The effects of Rho-kinase inhibition were partially mimicked by direct targeting of
actin-myosin contractions using a myosin-ATPase inhibitor. This demonstrated that
Rho-kinase is necessary during multiple stages of nephrogenesis and maturation, at least
in part, as a result of its ability to regulate actin-myosin contraction.
These results show that Rac1 and Rho-kinase play important roles during several aspects
of kidney development and highlights the significance of further investigating the
mechanisms involved during kidney organogenesis.|
|Keywords: ||metanephric kidney|
ureteric bud branching
|Appears in Collections:||School of Biomedical Sciences thesis and dissertation collection|
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