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Long form of latent TGF‐β binding protein 1 (Ltbp1L) regulates cardiac valve development
Author(s) -
Todorovic Vesna,
Finnegan Erin,
Freyer Laina,
Zilberberg Lior,
Ota Mitsuhiko,
Rifkin Daniel B.
Publication year - 2011
Publication title -
developmental dynamics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.634
H-Index - 141
eISSN - 1097-0177
pISSN - 1058-8388
DOI - 10.1002/dvdy.22521
Subject(s) - biology , transforming growth factor , microbiology and biotechnology , heart development , gene isoform , regulator , mesenchymal stem cell , homeostasis , medicine , endocrinology , anatomy , gene , biochemistry , embryonic stem cell
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 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‐β activity during valvulogenesis since its absence results in a perturbed Tgf‐β pathway that causes all Ltbp1L −/− valvular defects. Developmental Dynamics, 2011. © 2010 Wiley‐Liss, Inc.