ISOLATION OF NOVEL MUTATIONS AFFECTING THE MOUSE EMBRYO

Sloan-Kettering Institute For Cancer Res, New York NY

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Abstract

The genetic control of the events that shape the body plan of the mammalian embryo from the time of implantation until the basic body plan is laid out in midgestation is not well understood. During this time, the critical events of gastrulation, axis determination, germ layer determination and early differentiation of organ systems take place. Understanding the genetic control of these processes is crucial for progress in studies of human fertility and for the prevention of human birth defects. In this proposal, ENU mutagenesis will be used to identify a large set of new genes that control important events in mouse embryo between the time of gastrulation and midgestation in order to define the genetic pathways crucial in setting up the body plan of the mouse embryo. 50-100 new mutations that have clear effects on the morphology of the 9.5 dpc embryo will be identified and mapped. Two classes of genes will be studied in depth, those that control the organization of the body plan and those that affect dorsal-ventral patterning in the neural tube. For mutants that affect these processes, histological analysis, cell proliferation and cell death analysis and expression of molecular markers will be used to define the tissue and cellular abnormalities produced by the mutation. Two mutations, 5 and 118, that have already been isolated will be studied in depth. The line 5 mutation causes posterior truncation of the body axis, a preferential loss of axial and paraxial mesoderm, and failure of neural fold and somite formation; this combination of defects has not been observed in previously-characterized mutations. The line 5 mutation has been mapped to a 9 cM interval on chromosome 16 where no gene affecting this aspect of early development have been localized previously and therefore appears to define a new gene. Studies are proposed to define the primary defect leading to the line 5 phenotype. The line 118 mutation blocks neural tube closure, eye development and causes the formation of extra digits on the limbs. 118 appears to be allelic to the spontaneous mutation open-brain (opb), which has been shown to cause a ventral shift in cell fates in the neural tube. The gene responsible for the opb/118 phenotype will be molecularly cloned, using candidate gene or positional cloning approaches. Neural tube defects are one of the most common human congenital abnormalities and occur in approximately one out of 1000 births world-wide. Genetic studies in the mouse provide a unique and valuable source for understanding of the causes, means of detection, prevention and treatment of this class of human birth defects.