The broad goal of this proposal is to understand the influence of matrix chondroitin sulfate proteoglycans (CSPGs) on IHH and FGF signaling in the developing limb growth plate. Heparan sulfate proteoglycans are known to be essential for normal trafficking of and signaling by morphogens such as IHH. However, only recently have genetic means allowed observation of the distribution, movement and signaling efficiency of morphogens in a CSPG-deficient matrix. Through study of naturally occurring mutants deficient in CSPGs, we have demonstrated that: i) CSPGs are critical to limb development from the initial formation of the growth plate onward;ii) signaling by IHH and FGF is dependent on the presence of sulfated CSPGs in the matrix;iii) the effect of CSPG composition on morphogen signaling changes over the course of development. Now that we have developed conditional knock-down and over-expression transgenic mice to modify matrix CSPG composition, we are in a unique position to be able to test additional hypotheses regarding morphogen-matrix interactions.
Two specific aims will be pursued: 1) Determine how PAPS synthetase isoforms affect proteoglycan sulfation and thereby influence signaling during postnatal growth plate development. 2) Elucidate the mechanism by which absence of CSPG core protein or CS chains affects IHH and FGF signaling throughout growth development.
Trafficking of and signaling by secreted morphogens is critically important for the normal development of numerous tissue and organ systems. The proposed studies will enhance a new field focused on the regulation of key factors by the extracellular matrix environment through which these factors must migrate to deliver signals to target cells. Analyses of the novel genetic models outlined in this proposal will provide valuable insights into how abnormal matrix components cause disruption of morphogen signaling, thus contributing to the pathogenesis of certain developmental disorders.
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