(Taken directly from the application) This project aims to delineate genetic mechanisms which specify pattern and shape of the endochondral skeleton by focusing on a newly identified skeletogenic locus called bdytg. Mice homozygous for the bdytg mutation show a reduction in size and number of appendicular long bones, and hence the name brachydactyly (bdy, or short digit). This mutation, generated by transgene insertion, presents a ready means to identify a new skeletogenic factor and provides a unique opportunity to study its interaction with known bone regulators. Because developmental processes involved in skeletal formation are reiterated later during adult bone remodeling and repair, we hypothesize that this new factor may help elucidate the pathogenesis of various human skeletal syndromes. Moreover, it should provide insight into the design of new therapeutics to influence adult responses to bone injury or disease. Skeletal pattern is established and integrated at many levels during embryonic development beginning with the condensation of chondrogenic cells, progressing to segmentation of these condensations to form new cartilage elements, culminating in their ossification to generate an articulating skeleton. Despite the importance of segmentation in determining both bone shape and number, relatively little is known about the genes controlling it. This application sets out to fill this gap by cloning a new segmentation gene (bdytg) and placing it within the context of factors known to control skeletogenesis (e.g., BMPs, growth differentiation factors (GDFs), Hedgehogs, PTHrP, and cognate receptors).
Specific Aim 1 will identify the bdy gene and determine its function in chondrogenic growth and segmentation. Towards this aim we will: (1) identify the murine bdy gene (a candidate cDNA is already in hand); (2) determine the precise molecular nature of the bdytg mutation; (3) profile bdy expression during limb development; and (4) employ both gain-of-function and loss-of-function strategies to establish bdy function within the context of known skeletogenic signals.
Specific Aim 2 examines chondrogenic segmentation in wild-type and bdy mutant limbs, using both embryologic and histologic assays, along with current molecular genetic methods. These studies will order the bdy gene relative to key skeletogenic pathways (e.g., BMPs, GDFs, Ihh, PTHrP) and will address the mode of action of the bdytg allele, determining whether it functions in a cell autonomous or non-autonomous fashion.
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