From worms to frogs: Identifying conserved mechanisms of morphogenesis
Neural tube defects (NTDs) are a significant cause of perinatal and infant mortality. Neural tube closure involves complex and coordinated cell shape changes and tissue movements, folding a flat neuroepithelium into a tube. Mutations in over 250 genes lead to NTDs in mouse, yet aside from a few important examples, it is not known how mutations in these genes lead to NTDs. The complexity of neural tube closure and the large number of genes involved prompted us to consider using the small roundworm Caenorhabditis elegans to study NTD genes. C. elegans does not form a neural tube, but it is an ideal system for performing rapid functional assays, harnessing the strength of genetic and high-resolution live imaging studies. We propose that the early stage of C. elegans gastrulation (26-28 cells) represents a simple model of cell behaviors that occur in vertebrate neurulation, including actomyosin-dependent apical constriction and the formation of new cell-cell contacts during tissue closure (cell sealing). It is our central hypothesis that among the large list of NTD genes are some core regulators of conserved morphogenetic mechanisms, genes whose homologs may have parallel roles in a simple model, C. elegans gastrulation. Thus, we are screening through a complete set of NTD homologs in C. elegans by RNA interference, using a two-step sensitized screen that we developed to identify gastrulation genes. In C. elegans, gastrulation begins when two endodermal precursor cells, born on the outside of the embryo, undergo apical constriction and internalize. Through this screen, we have identified several NTD gene homologs that affect the internalization of the endodermal cells (see top left images in figure), suggesting that apical constriction may be disrupted. We are currently focusing on two of these genes – a transcription factor and a regulator of actin architecture. Published data have implicated each of these genes in mouse neural tube closure. However, the mechanistic bases for these NTDs are not well understood. We found that morpholinos against each of these genes disrupt neural tube closure in the frog X. laevis (see top right images), suggesting that these genes have conserved functions in neural tube closure across mammalian and non-mammalian species. We are currently studying these genes' functions in C. elegans by analyzing actomyosin and membrane dynamics in vivo, and we will use similar experiments in X. laevis (see bottom image) to test if the specific functions we identify are conserved during neural tube closure.
Jess' publications from her postdoc so far:
Honors and awards during Jess' postdoc:
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