Murine Lin-41 and let-7 genes in limb development

Yale University, New Haven CT

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Abstract

In Caenorhabditis elegans, genetics has revealed a dedicated pathway of genes, known as heterochronic genes that pattern the fourth axis of development, time. Heterochronic genes are the temporal analogs of the hox genes which pattern spatial dimensions (e.g. A/P, D/V axes) during development. Heterochronic mutants specify structures at the incorrect time relative to wild-type animals and therefore display striking developmental defects. Extremely little is known about temporal control of development in mammals, but since homologues to the heterochronic genes have recently emerged, we now have an opportunity (with the help of the YCCMD program) to extend the knowledge of developmental timing discovered in C. elegans to mammals, including humans. An emerging view is that universal mechanisms control development throughout phylogeny, for example, HOX clusters and signaling pathways. We propose to analyze the expression pattern and loss of function phenotype of the mammalian let-7 and lin-41 genes. We find that mouse lin-41 is expressed in the limb bud and the somites. Patterning the proximal-distal axis of the vertebrate limb, and patterning of the somites are both known to be under temporal control, but are poorly understood. We are in a unique and opportune position to test whether the mammalian heterochronic genes function in control of limb and somite development.