Research Synopsis
Our lab is interested in how the mammalian body plan is generated during early pregnancy. We seek to undertand the mechanisms which establish and pattern the body axes and organ precursors of the embryo. We are using the unique genetic technologies available in the mouse to study induction, pattern formation, and morphogenesis, particularly of the neural tube and surrounding axial skeleton.
One approach underway is the targeted mutation or misexpression of candidate genes likely to control these events. Many of these genes function analogously in the development of other organisms, allowing us to exploit the experimental strengths of other model systems to devise better mouse experiments. We also use existing mutant and transgenic mice to probe the roles of cellular and molecular interactions in tissue development. Our studies bear on normal mammalian embryogenesis and on its anomalies, such as human birth defects of the neural tube and skeleton.
Projects underway focus primarily on the role of molecules initially identified as important embryonic "organizer" genes. These are genes thought to encode the activities of Spemann's organizer, which is a small group of cells believed to be the source of the signals which induce and pattern many of the primary tissues of the vertebrate embryo. For example, the organizer is presumed to induce neural tissue from naïve ectoderm and to confer anterior to posterior pattern within it. Surprisingly, we have found that mutant mouse embryos lacking the organizer nevertheless develop a neural tube with correct anterior-posterior patterning. Moreover, when we delete the gene encoding a presumed organizer neural-inducing signal, we see no effect on neural development, but rather skeletal abnormalities in the head and neck of newborns. Deletion of the known neural-inducing signals simultaneously still results in embryos with normal neural induction, though subsequent inductive events are disrupted. Our results show that neural induction in mammals is more complex than models based on lower vertebrates suggest, and imply the existence of other means of neural induction and patterning. We are pursuing several complementary strategies to reveal the molecular and cellular bases for these phenomena.
Meanwhile, we find that these
organizer genes have essential roles in development of specific organs
and structures arising later in embryogenesis, including the forebrain,
the craniofacial skeleton, the heart, and several other critical organs.
We have obtained phenotypes in our various mutant combinations which very
closely resemble two severe human malformation syndromes. Because of the
excellent embryological tools available in the mouse, we are now able to
address the cellular and molecular defects underlying these birth defects.
Our ongoing work on early axial patterning has thus led us into clinically-relevant
research on the etiology of important congenital malformations.
