BMP/SMAD1 signaling sets a threshold for the left/right pathway in lateral plate mesoderm and limits availability of SMAD4

Abstract

The left/right (LR) axial pathway establishes asymmetry in the patterning and morphogenesis of multiple internal organs, including the heart. In mammals, this pathway involves the breaking of molecular symmetry in or around the node, transfer of asymmetry information to the lateral plate mesoderm (LPM), propagation of molecular asymmetries throughout the LPM, and interpretation of these signals for proper organ morphogenesis (Nonaka et al. 2002). Recent experiments have demonstrated that the breaking of bilateral symmetry in the mouse node occurs via a process termed "nodal flow," in which motile cilia in the node generate leftward movement of molecular determinants via lipoprotein vesicles (Hirokawa et al. 2006;. NODAL, a transforming growth factor ␤ (TGF␤) superfamily member, is a key molecule in the LR cascade. NODAL acts first in mesoderm specification and anterior-posterior axis formation, signaling through a membrane complex containing type I and II TGF␤ serine/ threonine kinase receptors, as well as GPI-anchored members of the EGF-CFC family. This complex phosphorylates intracellular SMAD2 and SMAD3, which associate with the common TGF␤/NODAL/BMP (bone morphogenetic protein) pathway SMAD, SMAD4, and forkhead transcription factor FOXH1, to regulate downstream target genes (Shen 2007). In the LR pathway,

An Atypical Canonical Bone Morphogenetic Protein (BMP) Signaling Pathway Regulates Msh Homeobox 1 (Msx1) Expression during Odontogenesis

“…In line with these observations are several previous studies on the competitive binding of Smad4 between pSmad1/ 5/8 and pSmad2/3. It was shown that pSmad1 inhibited TGF␤-ALK5/pSmad2 pathway, and overexpression of Smad4 reversed the inhibition completely, indicating a competition between pSmad2 and pSmad1 for limited amounts of their common transcriptional cofactor Smad4 (29). TGF␤ stimulation could result in a decrease in pSmad1/5-Smad4 complexes formed in response to BMP and an increase in pSmad2/3-Smad4 complexes (30).…”

“…Activin/nodal ligands induce activation of Smad2 and Smad3. It was also reported that BMP and activin/nodal signaling pathways antagonize each other through competition between Smad1 and Smad2 for their binding to the common component Smad4 (29,49,50).…”

Smad2 Is Essential for Maintenance of the Human and Mouse Primed Pluripotent Stem Cell State

“…Additionally, competition between BMP-activated Smads and TGF-␤/activin Smads may control Nanog expression (35). This antagonism may be explained by competition for Smad4 (57) or heteromeric Smad combinations in transcription regulation (64). How Smad2 represses BMP signaling in the control of stem cell pluripotency remains to be further defined.…”

Human Heterotaxy Syndrome

“…Chordin and noggin, which are BMP signaling antagonists, promote Nodal signaling around the node, while BMP signaling represses Nodal expression in the left LPM. 52, 53 The Nodal signaling pathway is mediated by an activin receptor complex composed of a dimmer of the type I activin receptor, ActRIB, and a dimeric type II receptor, Act-RII or ActRIIB. 54 Different from conventional Activin signaling, the Nodal pathway requires activities of membrane-bound EGF-CFC co-receptors, Cripto and Cryptic.…”