Monday, October 10th
at 12 noon in Aresty Auditorium
Lee Niswander, PhD
Howard Hughes Medical Institute Investigator and Professor,
University of Colorado, USA
“Exploring Neural Tube Closure via Genes, Environment, and Imaging”
Click Here to Watch the Live Webcast!
A light lunch will be served in the foyer at 11:45 am
Abstract: Neural tube closure requires the coordination of multiple tissues (neural ectoderm, the neighboring mesenchyme and overlying ectoderm), in both space and time, and these tissues undergo highly complex morphogenetic movements. Defects in any of these processes can lead to neural tube defects (NTDs). To identify the genes involved in this complicated process, our lab has undertaken ENU mutagenesis and forward genetic screens in mice. Over the years we have identified a large number of novel genes that are critical for neural tube closure and determined their mechanisms of action. Examples from some of our recent work will be given.
The etiology of NTDs is complex and involves both genetic and environmental factors. Mouse NTD models have enormous potential to aid in understanding the genetics underlying responsiveness or non-responsiveness to environmental factors. The most effective environmental influence in decreasing the risk for NTDs in humans is folic acid (FA) fortification. However, only a few mouse models have been tested for FA responsiveness and very little is known of the mechanisms underlying FA action or the extent to which molecular pathway information can be applied to determine which mutations may be environmentally sensitive. The Niswander lab is exploring the relationship between genes and responsiveness to FA supplementation using mouse models that are unrelated to the FA metabolism pathway. Although FA supplementation is clearly efficacious in reducing human and mouse NTD incidence, contrary to expectations, we found that some mouse genetic mutants respond in a surprisingly negative way to FA supplementation, showing an increased incidence of NTDs in homozygous mutants, occurrence of NTDs in heterozygous embryos and embryonic lethality prior to NT closure. Furthermore, we found that, for the same genetic allele, NTD risk can depend on the length of FA exposure. Our unexpected findings highlight the need to understand how FA influences NT closure and the mechanisms and genetics underlying the response to FA supplementation.
Neural tube morphogenesis is highly dynamic, yet has largely been studied in static images. Our lab has coupled the ability to culture the mouse embryo during the process of neural tube closure with confocal imaging technology and fluorescent reporter lines to provide a dynamic view of NT closure in a living mammalian embryo. This allows a real-time visualization of cell movements and behaviors during NT morphogenesis in the mouse. We are now coupling live imaging with our genetic mutants to visualize how these genetic changes affect the cell behaviors of NT closure.
Host: Dr. Gage Crump
