Developmental Expression of Latent Transforming Growth Factor β Binding Protein 2 and Its Requirement Early in Mouse Development

Abstract

Latent transforming growth factor ␤ (TGF-␤) binding protein 2 (LTBP-2) is an integral component of elastin-containing microfibrils. We studied the expression of LTBP-2 in the developing mouse and rat by in situ hybridization, using tropoelastin expression as a marker of tissues participating in elastic fiber formation. LTBP-2 colocalized with tropoelastin within the perichondrium, lung, dermis, large arterial vessels, epicardium, pericardium, and heart valves at various stages of rodent embryonic development. Both LTBP-2 and tropoelastin expression were seen throughout the lung parenchyma and within the cortex of the spleen in the young adult mouse. In the testes, LTBP-2 expression was seen within lumenal cells of the epididymis in the absence of tropoelastin. Collectively, these results imply that LTBP-2 plays a structural role within elastic fibers in most cases. To investigate its importance in development, mice with a targeted disruption of the Ltbp2 gene were generated. Ltbp2 ؊/؊ mice die between embryonic day 3.5 (E3.5) and E6.5. LTBP-2 expression was not detected by in situ hybridization in E6.5 embryos but was detected in E3.5 blastocysts by reverse transcription-PCR. These results are not consistent with the phenotypes of TGF-␤ knockout mice or mice with knockouts of other elastic fiber proteins, implying that LTBP-2 performs a yet undiscovered function in early development, perhaps in implantation.

Expression and matrix deposition of latent transforming growth factor β binding proteins in normal and fibrotic rat liver and transdifferentiating hepatic stellate cells in culture

“…This conclusion is supported by the recent finding that only LTBP-1, but not LTBP-2, is able to bind to the small, latent TGF-␤ complex. 14 The fact that LTBP-2 knockout mice are lethal during early development 51 proposes fundamental, TGF-␤-unrelated functions of this protein, possibly in the structural remodeling of the extracellular matrix.…”

Bone defects in latent TGF-beta binding protein (Ltbp)-3 null mice; a role for Ltbp in TGF-beta presentation

“…Matrix deposition appears to be covalent as LTBP-1 can only be incorporated in the presence of cells or cell products and most of the matrix-associated LTBP-1 can only be released by proteases (Taipale et al 1995, Unsold et al 2001. LTBP-2 is found predominantly as a component of elastic fibrils and has a much more restricted cellular distribution than LTBP-1 (Gibson et al 1995, Shipley et al 2000. LTBP-3 expression has been observed in osteoblasts and periosteal cells, endothelial cells, and a number of other cell types in developing embryos (Yin et al 1995), whereas LTBP-4 is secreted by fibroblasts (Saharinen et al 1998).…”

“…An LTBP-2 null mouse has been described with a severe embryonic lethal phenotype at embryonic day 3·5-6·5 (Shipley et al 2000). The reason for lethality is not clear but is not related to TGF-availability, because LTBP-2 does not bind the growth factor.…”

Latent TGF-β binding protein 4 promotes elastic fiber assembly by interacting with fibulin-5

“…In addition to tropoelastin and lysyl oxidase-like enzymes, fibulin-5 interacts with several other molecules, such as integrins (13,17,18), elastin microfibril interface located protein (EMILIN) (19), apolipoprotein(a) (20), extracellular superoxide dismutase (21), LTBP-2 (22), and fibrillin-1 (23). However, these interactions do not account for the fiber organizing function of fibulin-5, because mice deficient in these molecules do not phenocopy Fbln5 knockout mice (24)(25)(26)(27).…”