DEVELOPMENTAL ACTIVITIES OF LATENT TGF-B BINDING PROTEIN

New York University School Of Medicine, New York NY

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Abstract

The latent TGF-beta binding proteins (LTBP) comprise a family of four structurally related proteins that were originally described as part of the latent TGF-beta complex consisting of the TGF-beta dimer, the TGF-beta propeptides noncovalently bound to TGF-beta, and LTBP is thought to help control the activation of latent TGF- beta and to ensure that TGF-beta is released at the correct place and time. In order to gain insight into the functional role(s) of the LTBPs, we have created an LTBP-3 null mouse. This mouse has skeletal and cranial abnormalities that are similar to those observed in achondroplasia and Cruzon syndrome. To characterize potential roles for LTBPs in early development we have examined the distribution and function of LTBP-1 and -3 in Xenopus embryos. The distribution of LTBP-3 is restricted primarily to the cranial region. LTBP-1 has a widespread distribution, and in the early embryo its distribution is similar to that of proteins expressed by Spemann's organizer and that are responsible for dorsal patterning in the developing embryo. We have observed that expression of a truncated form of LTBP-1 in ventral cells of early embryos results in secondary dorsal axis formation in the ventral region. In this application, we propose three aims designed to clarify the role of LTBPs in development. In Aim 1 we will explore the molecular mechanism for the skeletal abnormalities in LTBP-3-/- mice. We will test the hypothesis that the phenotype results from excess formation of active TGF- beta in the absence of the normal binding protein by utilizing in vitro and in vivo approaches coupled with mouse molecular genetics. In Aim 2 we will address possible redundancy and/or functional ovelap within the LTBP family by generating an LTBP-4- /- mouse. This animal will be studied together with LTBP-3 and LTBP-1 null animals to discern the relative contributions of specific family members to mouse physiology. In Aim 3 we will characterize the role of LTBP-1 in Xenopus embryo patterning. We will characterize the mechanism of dorsalization, the ligand bound, the mechanism of binding, and how this contributes to early patterning. In sum, the experiments outlined will yield information on the fundamental biology of LTBP. This information may have relevance in understanding developmental events in connective tissues.