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Long form of latent TGF-? binding protein 1 (Ltbp1L) regulates cardiac valve development.

ABSTRACT: Transforming Growth Factor ? (TGF-?) is crucial for valve development and homeostasis. The long form of Latent TGF-? binding protein 1 (LTBP1L) covalently binds all TGF-? isoforms and regulates their bioavailability. Ltbp1L expression analysis during valvulogenesis revealed two patterns of Ltbp1L production: an early one (E9.5-11.5) associated with endothelial-to-mesenchymal transformation (EMT); and a late one (E12.5 to birth) contemporaneous with valve remodeling. Similarly, histological analysis of Ltbp1L(-/-) developing valves identified two different pathologies: generation of hypoplastic endocardial cushions in early valvulogenesis, followed by development of hyperplastic valves in late valvulogenesis. Ltbp1L promotes valve EMT, as Ltbp1L absence yields hypoplastic endocardial cushions in vivo and attenuated EMT in vitro. Ltbp1L(-/-) valve hyperplasia in late valvuogenesis represents a consequence of prolonged EMT. We demonstrate that Ltbp1L is a major regulator of Tgf-? activity during valvulogenesis since its absence results in a perturbed Tgf-? pathway that causes all Ltbp1L(-/-) valvular defects.

SUBMITTER: Todorovic V

PROVIDER: S-EPMC3012267 | biostudies-literature | 2011 Jan

REPOSITORIES: biostudies-literature

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Long form of latent TGF-β binding protein 1 (Ltbp1L) regulates cardiac valve development.

Todorovic Vesna V Finnegan Erin E Freyer Laina L Zilberberg Lior L Ota Mitsuhiko M Rifkin Daniel B DB

Developmental dynamics : an official publication of the American Association of Anatomists 20110101 1

Transforming Growth Factor β (TGF-β) is crucial for valve development and homeostasis. The long form of Latent TGF-β binding protein 1 (LTBP1L) covalently binds all TGF-β isoforms and regulates their bioavailability. Ltbp1L expression analysis during valvulogenesis revealed two patterns of Ltbp1L production: an early one (E9.5-11.5) associated with endothelial-to-mesenchymal transformation (EMT); and a late one (E12.5 to birth) contemporaneous with valve remodeling. Similarly, histological analy ...[more]

PMID: 21181942

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Project description:The four-chambered mammalian heart develops from two fields of cardiac progenitor cells distinguished by their spatiotemporal patterns of differentiation and contributions to the definitive heart. The first heart field differentiates earlier in lateral plate mesoderm, generates the linear heart tube and ultimately gives rise to the left ventricle. The second heart field (SHF) differentiates later in pharyngeal mesoderm, elongates the heart tube, and gives rise to the outflow tract and much of the right ventricle. Because hearts in lower vertebrates contain a rudimentary outflow tract but not a right ventricle, the existence and function of SHF-like cells in these species has remained a topic of speculation. Here we provide direct evidence from Cre/Lox-mediated lineage tracing and loss-of-function studies in zebrafish, a lower vertebrate with a single ventricle, that latent TGF-? binding protein 3 (ltbp3) transcripts mark a field of cardiac progenitor cells with defining characteristics of the anterior SHF in mammals. Specifically, ltbp3(+) cells differentiate in pharyngeal mesoderm after formation of the heart tube, elongate the heart tube at the outflow pole, and give rise to three cardiovascular lineages in the outflow tract and myocardium in the distal ventricle. In addition to expressing Ltbp3, a protein that regulates the bioavailability of TGF-? ligands, zebrafish SHF cells co-express nkx2.5, an evolutionarily conserved marker of cardiac progenitor cells in both fields. Embryos devoid of ltbp3 lack the same cardiac structures derived from ltbp3(+) cells due to compromised progenitor proliferation. Furthermore, small-molecule inhibition of TGF-? signalling phenocopies the ltbp3-morphant phenotype whereas expression of a constitutively active TGF-? type I receptor rescues it. Taken together, our findings uncover a requirement for ltbp3-TGF-? signalling during zebrafish SHF development, a process that serves to enlarge the single ventricular chamber in this species.

Dataset Information

Long form of latent TGF-? binding protein 1 (Ltbp1L) regulates cardiac valve development.

Publications

Long form of latent TGF-β binding protein 1 (Ltbp1L) regulates cardiac valve development.

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