Thomas F. Vogt
Department of Pharmacology, Merck Research Laboratories
Merck Research Laboratories
33 Avenue Louis Pasteur
Boston, MA 02115
1992 Searle Scholar
Mouse Developmental GeneticsA fundamental and fascinating biological process is the development of a fertilized egg into a multicellular animal. Our laboratory is investigating the genetic program that guides this process of differentiation and spatial organization by study ing mouse limb development. During embryogenesis, the limb bud develops as a result of a number of inductive interactions that occur between regionalized groups of ectodermal and mesodermal cells. Embryological studies suggest that these interactions result in the establishment of positional identities for cells in terms of their anterior-posterior, proximal-distal, and dorsal-ventral location. The culmination of these events is the patterned arm and leg. Our approach to determine the molecular mechanisms underlying the generation of this spatial information is to characterize mutations that disrupt this process.
Positional cloning of limb mutants. The emergence this century of the mouse as the mammal of choice for genetic, developmental, and cancer studies has led to a large collection of mouse mutations with interesting phenotypes. We are studying mutations that affect the anterior-posterior patterning of the limb. These include the limb deformity (ld), Strong's luxoid (Lst), and Ulnaless (Ul) mutants. The ld mutation is recessive and results in a fusion of the distal limb bones and a reduction in the number of digits. In contrast, the Lst and Ul mutations are dominant and result in a duplication of the distal bones and digits in the case of Lst, or the absence of the ulna and fibula in the case of Ul heterozygotes. These mutations are pleiotropic and affect the development and patterning of other body structures. All three of these mutations are closely linked on Chromosome 2 of the mouse genetic map. The availability of a high density genetic map and the ability to clone and analyze large physical segments of genomic DNA makes the molecular cloning of these loci fea sible, and has been accomplished for the ld gene. To complement our molecular genetic approaches, we are performing embryological studies to describe the spatial and temporal onset of the phenotype in mutant embryos. In addition, by mating mice with different limb mutations we hope to order these genes in an epistasis pathway.
Growth factors in development. A complement to our ongoing investigations of existing limb mutants is the evaluation of cloned genes as candidates for impor tant functional roles in limb morphogenesis. Results in a variety of animals have demonstrated that secreted growth factors and their receptors play important roles during development. Many studies have suggested that retinoic acid or a retinoic acid responsive signal(s) originating from the posterior cells of the embryonic limb may confer anterior-posterior information. The midkine growth factor, Mdk, has many properties that suggest it as an excellent candidate for a signaling molecule in the limb. The Mdk gene is induced by retinoic acid; it is expressed in many places during embryogenesis where inductive signaling is occurring, including the limb bud; its product is a secreted molecule able to modify the behavior of cells. We have mapped the Mdk gene to a position on mouse Chromosome 2, where it is a candi date gene for the Ul mutant. Using embryonic stem cells and transgenic techniques, we are attempting to create and study Mdk loss- and gain-of-function mutations to address its function in development. In addition, we are exploring the upstream regulation of Mdk by retinoic acid and its downstream targets by experimental approaches designed to identify its receptor. These general strategies will be applied to other candidate genes implicated in mouse development.
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