Genetic basis of limb and gut development and dysmorphogenesis

Aberrant organ development leads to human congenital abnormalities. We are investigating the processes of normal organ development and attempting to uncover the events that go wrong resulting in birth defects. One field of interest is the development of the limbs. Each year a large number of infants are born with defects of the arms and/or legs and we are studying a subset which manifest extra fingers and toes. We have identified the genetic mutations that constitute the molecular basis for the defect and propose to investigate how these mutations give rise to hands and feet abnormalities. A second interest is in the region of the viscera that includes the stomach, pancreas, spleen and small intestine. These organs are under strict left/right instructions to grow to one side of the body cavity. When the process of left/right patterning is disrupted a number of abnormalities occur including cardiac and gastrointestinal defects and often congenital loss of the spleen. We propose to study the processes that control the genesis and the placement of these organs.

Mouse model systems provide insights into the process of organ development. The goals of these studies are to examine mouse mutants that model congenital abnormalities in order to understand both the normal processes that are responsible for organogenesis and the abnormalities that disrupt development and lead to disease.||Focusing on the genetics of the mouse, we examine two aspects of development. Firstly, we explore the mechanisms essential for normal skeletal development. In particular, we investigate limb patterning mechanisms required to generating the array of skeletal elements that constitute the mammalian limb. Expression of the Shh gene is central to the mechanism that patterns the limb. Correct spatio-specific Shh expression is required for normal patterning of the digits. We investigate the mechanisms for the long-range spatiotemporal regulation of Shh and the mechanism by which point mutations residing in the regulator manifests PPD (preaxial polydactyly). We propose to identify sequence elements which may interact with the ZRS and attempt to establish factors required for regulating expression through the ZRS. In addition we propose to use the ZRS as a tool to explore the molecular mechanisms required for patterning the mammalian limb.||Secondly, we investigate the development of the gut; in particular, mechanisms that define the left-right asymmetry of organ systems. One aspect is to focus on the spleno-pancreatic region. These studies give insights into mesodermal/ endodermal interactions important for directing early gut development. We have hypothesized that the splanchnic mesoderm-derived SMP, by coordinating mesenchymal functions, plays a role in the morphogenesis of the gut region which includes the stomach, duodenum, pylorus, and pancreas. The Bapx1 gene resides near or at the top of a hierarchy of genes that controls morphogenesis in this region. The mesenchyme in which these genes are expressed is crucial in sending morphogenetic signals to the endoderm. The mesenchyme specifically grows to the left under the control of the SMP which itself is controlled by the L/R signalling cascade. We plan to investigate the mesenchymal signals regulated by BAPX1 that signal to the endoderm to define the stomach/duodenal boundary, and regulate the rate of cell division. We also plan to investigate the Bapx1 role that is crucial later in development to define an important boundary between the spleen and pancreas. In the absence of this boundary differentiated pancreatic acini are induced to transform to ectopic gut-like structures.||Finally, we have made a mouse model for the Matthew Woods syndrome (or PDAC syndrome) which effects heart asymmetry, lung and visceral development and patients that survive are mentally retarded. The mutation affects retinoic acid signalling and we are investigating the role of the gene on development.