Cellular Mechanisms Controlling Neural Crest Cell Migration Along The Developing Gut
Funder
National Health and Medical Research Council
Funding Amount
$368,895.00
Summary
Within the wall of the gut, there are a large number of neurons, probably more than are in the spinal cord. These enteric neurons play an essential role in controlling a number of gut functions including peristalsis (the propulsion of contents along the gut). Most of the neurons in the gut, including those in the large intestine, arise from precursors that emigrate from the hindbrain, and then migrate into and along the gastrointestinal tract during development. The colonization of the gut by ne ....Within the wall of the gut, there are a large number of neurons, probably more than are in the spinal cord. These enteric neurons play an essential role in controlling a number of gut functions including peristalsis (the propulsion of contents along the gut). Most of the neurons in the gut, including those in the large intestine, arise from precursors that emigrate from the hindbrain, and then migrate into and along the gastrointestinal tract during development. The colonization of the gut by neuron precursors takes 5 days in mice and 6 weeks in humans. Studies of the mechanisms controlling the migration of neuron precursors along the gut have provided fundamental information about cell migration in general. Genetic studies in humans and mice have identified some of the genes that are necessary for the migration of neuron precursors along the gastrointestinal tract, but for some of the key genes, their precise role is unknown. We have recently developed a method for imaging living neuron precursors migrating through explants of embryonic mouse gut. In the current proposal we will meld imaging and genetic studies to understand how mutations in particular genes lead to migration defects. In particular, how do particular mutations affect the migratory behaviour of enteric neural precursors? We have also previously shown that neuron precursors migrate along the gut in close association with axons. We will examine the nature of these interactions - in particular, who is following whom, and what happens when cell migration and axon growth are uncoupled? These studies, which will investigate a number of critical aspects of the migration of neural precursors into and along the developing gut, are central to understanding how the enteric nervous system is established along the gastrointestinal tract.Read moreRead less
Neogenin Regulates Progenitor Division And Interneuron Migration In The Developing Forebrain
Funder
National Health and Medical Research Council
Funding Amount
$526,878.00
Summary
In humans, mutations in genes controlling the production of new neurons in the embryonic brain result in severe disruption of the adult cortex. This project tests the hypothesis that one cell surface molecule, Neogenin, regulates the birth of new neurons and their subsequent travels through the developing brain to form the neocortex. The outcome of these studies will provide fundamental insights into the aberrant processes that underlie human mental retardation, epilepsy, dyslexia and autism.
Olfactory Ensheathing Cells: A Major Contributor To Axon Guidance?
Funder
National Health and Medical Research Council
Funding Amount
$575,749.00
Summary
The olfactory (smell) system is a unique part of the nervous system because nerve cells are generated throughout life. Understanding how the olfactory system grows and regenerates may lead to therapeutic approaches to repair other regions of the nervous system. This project will use high resolution digital time-lapse imaging of living nerve cells and the specialised cells called olfactory ensheathing cells to determine how the behaviour of these cells can be manipulated to improve regeneration.
Regulation Of Epithelial Migration By Scribble In Development And Wound Repair
Funder
National Health and Medical Research Council
Funding Amount
$516,078.00
Summary
The movement of epithelial cells within our body (the cells that form the thin protective layer on exposed bodily surfaces such as skin and the lining of internal cavities, ducts, and organs) is essential for our normal embryonic development as well as for healing of wounds following injury. Understanding how this movement is regulated is therefore a fundamental area of medical biology. Although much is known about the mechanics of how a cell moves, the signals used to coordinate this movement s ....The movement of epithelial cells within our body (the cells that form the thin protective layer on exposed bodily surfaces such as skin and the lining of internal cavities, ducts, and organs) is essential for our normal embryonic development as well as for healing of wounds following injury. Understanding how this movement is regulated is therefore a fundamental area of medical biology. Although much is known about the mechanics of how a cell moves, the signals used to coordinate this movement so as to ensure that each cell migrates to the right place during embryonic development or in response to a wound is not well understood. A number of lines of evidence suggest that proteins required for the correct orientation of cells within our body (a property of cells known as polarity) may be essential for this process. Mutation of the polarity protein Scribble in the fly, zebrafish and mouse causes a disorganization of epithelial tissues during embryonic development. We have now shown that Scribble is required for cells to orientate correctly so as to be able to move in response to a wound in tissue culture and also during embryonic development and wound healing in the mouse. It is currently unknown how Scribble regulates migration. Here we propose to identify the molecules that Scribble regulates to coordinate cell movement during development and tissue repair. These studies will provide new insights into the fundamental process of how cell movement is coordinated and could lead to novel strategies for improved treatment of tissue injuries.Read moreRead less
The Role Of Netrin-DCC In The Development Of The Corpus Callosum
Funder
National Health and Medical Research Council
Funding Amount
$512,065.00
Summary
During embryonic development neurons send out axons that connect to other target neurons within the brain. The proper connectivity of these axons is vital to brain function. The largest axon tract in the brain is called the corpus callosum and connects neurons in the left and right cerebral hemispheres. When the corpus callosum does not form, significant cognitive, motor and sensory deficits occur in patients. This condition, known as agenesis of the corpus callosum (ACC), is associated with ove ....During embryonic development neurons send out axons that connect to other target neurons within the brain. The proper connectivity of these axons is vital to brain function. The largest axon tract in the brain is called the corpus callosum and connects neurons in the left and right cerebral hemispheres. When the corpus callosum does not form, significant cognitive, motor and sensory deficits occur in patients. This condition, known as agenesis of the corpus callosum (ACC), is associated with over 50 different human congenital syndromes. Thus understanding how the genes and molecules involved in the formation of the corpus callosum function in normal development can provide the basis for our understanding of what goes wrong in ACC. In this proposal we will investigate the role of the axon guidance molecule Netrin1, and its receptor DCC, in development of the corpus callosum in both a mouse model and in humans with malformations of the corpus callosum. Although Netrin1-DCC signalling has traditionally been associated with mechanisms of axon guidance, we hypothesize that these molecules may play a different role, specifically in cellular adhesion and ultimately in the fusion of the two cerebral hemispheres, in a manner that allows the corpus callosum to form. A second role for Netrin1-DCC signalling may be in the guidance of these axons once the midline has fused correctly and we investigate this in Aim 2 of the proposal. Finally, we are collaborating with a paediatric neurologist at UCSF, who has identified several mutations in the DCC gene in patients with ACC. In Aim 3 we test whether these mutations disrupt the function of DCC in callosal axon pathfinding. Understanding how these genes function during development of the brain and how their function may be altered in ACC is crucial to providing a proper diagnosis and prognosis for these patients. Ultimately, understanding more about how these genes function could also lead to prevention of these disorders.Read moreRead less
The Role Of The Suppressors Of Cytokine Signalling 6 And 7 In Cerebral Cortex Development
Funder
National Health and Medical Research Council
Funding Amount
$377,189.00
Summary
Defects in neuronal cell migration during embryonic development lead to mental retardation and epilepsy. Although neuronal migration is essential for the development of normal intelligence, we know relatively little about the molecular mechanisms that regulate this process. We have identified two proteins, Socs6 and Socs7, which are essential for neuronal migration and normal cerebral cortex development. We propose to fully investigate the function of Socs6 and Socs7 during cortex development.