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Fat PCP signalling and skeletal morphogenesis

Reference	BB/G021074/1
Principal Investigator / Supervisor	Professor philippa Francis-West
Co-Investigators / Co-Supervisors
Institution	King's College London
Department	Craniofacial Dev Orthodon and Microbiol
Funding type	Research
Value (£)	402,840
Status	Completed
Type	Research Grant
Start date	01/12/2009
End date	30/05/2013
Duration	42 months

Abstract

A fundamental outstanding question in developmental biology is how the shape of the skeletal elements in vertebrates is determined. We have evidence that planar cell polarity (PCP) signalling pathways, which control the polarisation of cells within a tissue, play a significant role. Two PCP pathways have been identified in Drosophila, the Frizzled PCP (Fz-PCP) and the Fat-PCP pathways. It is well established that the Fz-PCP pathway is conserved in vertebrates where it regulates cell movements and orientated cell divisions to control the morphogenesis of many tissues. Very recently, the Fat-PCP pathway has also been shown to control PCP signalling events in vertebrates. The Fat-PCP pathway involves Fat, Dachsous and FjX1. The role of these PCP pathways in skeletal morphogenesis has not been investigated. We have analysed the skeletal phenotypes of Dchs1 mutant mice, a component of the newly identified PCP pathway in vertebrates, and have found that they have sternum and vertebral defects. Similar abnormalities occur in the Vangl2 mutant, which has a mutation in a core component of the Fz-PCP pathway. This argues for an unsuspected role of PCP signalling during axial skeletal morphogenesis. The aim of this proposal is to determine the role of PCP signalling, that is orientated cell movements and cell divisions, during morphogenesis of the skeleton. We will determine how these are affected in the Dchs1, Fat4 and Vangl2 mouse mutants. We will also use the developing chick embryo to analyse how Fat-PCP signalling regulates cellular polarity and movement using time-lapse video confocal microscopy. Finally, we will examine Fat4/Dsch1, Dsch1/FjX1, and Fat4/FjX1 double mutants, which will provide insight into whether these genes act in a simple signalling pathway in vertebrates, as in Drosophila. This proposal will identify the contribution of the two PCP signalling pathways during morphogenesis of skeletal structures, an unresolved question in developmental biology

Summary

During embryonic development the orientation of structures such as the hairs of our skin is controlled by a pathway known as the planar cell polarity (PCP) pathway. In fruitflies, where PCP signaling also controls the orientation of hairs and bristles, two pathways are known to be important: the frizzled PCP pathway and the Fat-PCP pathway. In vertebrates, including humans, the role of the frizzled PCP pathway is well known where, for example, it controls the orientation of hair cells within the inner ear enabling us to hear and the orientation of cell divisions in the kidney which allow the kidney tubules to extend and function properly. In addition, this pathway controls cell movement/shape changes allowing the extension of our body axis during development. When this does not take place properly, the neural tube (the developing spinal cord can not close). Recently, it was shown that the Fat-PCP pathway is important in not only fruitflies but in vertebrates e.g. humans and mice and also controls the orientation of structures and that defects could result in hearing defects and cystic kidney disease. By removing the function of dachsous, part of the Fat-PCP pathway in mice, we have shown that in addition to kidney and inner ear defects, the vertebrae and sternum do not develop properly. We now aim to determine how this pathway controls the morphogenesis (the shape) of the skeleton. Nothing is known about how the shape of our bones is determined, but the PCP pathways are very strong candidates to control morphogenesis. We think that PCP signalling will control the orientation of cell divisions which will allow a bone to expand in a particular direction and the movement of the skeletal cells to create the correct bone shape and we plan to investigate this idea by asking how the cells divide and change shape in developing skeletal structures when the Fat PCP pathway is not working.

Committee	Closed Committee - Genes & Developmental Biology (GDB)
Research Topics	X – not assigned to a current Research Topic
Research Priority	X – Research Priority information not available
Research Initiative	X - not in an Initiative
Funding Scheme	X – not Funded via a specific Funding Scheme

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