title: BMP/SMAD1 signaling sets a threshold for the left/right pathway in lateral plate mesoderm and limits availability of SMAD4.
abstract: Bistability in developmental pathways refers to the generation of binary outputs from graded or noisy inputs. Signaling thresholds are critical for bistability. Specification of the left/right (LR) axis in vertebrate embryos involves bistable expression of transforming growth factor beta (TGFbeta) member NODAL in the left lateral plate mesoderm (LPM) controlled by feed-forward and feedback loops. Here we provide evidence that bone morphogenetic protein (BMP)/SMAD1 signaling sets a repressive threshold in the LPM essential for the integrity of LR signaling. Conditional deletion of Smad1 in the LPM led to precocious and bilateral pathway activation. NODAL expression from both the left and right sides of the node contributed to bilateral activation, indicating sensitivity of mutant LPM to noisy input from the LR system. In vitro, BMP signaling inhibited NODAL pathway activation and formation of its downstream SMAD2/4-FOXH1 transcriptional complex. Activity was restored by overexpression of SMAD4 and in embryos, elevated SMAD4 in the right LPM robustly activated LR gene expression, an effect reversed by superactivated BMP signaling. We conclude that BMP/SMAD1 signaling sets a bilateral, repressive threshold for NODAL-dependent Nodal activation in LPM, limiting availability of SMAD4. This repressive threshold is essential for bistable output of the LR system.
authors.affiliation: Victor Chang Cardiac Research Institute, Darlinghurst, New South Wales, Australia.
authors.forename: Milena B
authors.initials: MB
authors.lastname: Furtado
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Solloway
authors.forename: Vanessa J
authors.initials: VJ
authors.lastname: Jones
authors.forename: Mauro W
authors.initials: MW
authors.lastname: Costa
authors.forename: Christine
authors.initials: C
authors.lastname: Biben
authors.forename: Orit
authors.initials: O
authors.lastname: Wolstein
authors.forename: Jost I
authors.initials: JI
authors.lastname: Preis
authors.forename: Duncan B
authors.initials: DB
authors.lastname: Sparrow
authors.forename: Yumiko
authors.initials: Y
authors.lastname: Saga
authors.forename: Sally L
authors.initials: SL
authors.lastname: Dunwoodie
authors.forename: Elizabeth J
authors.initials: EJ
authors.lastname: Robertson
authors.forename: Patrick P L
authors.initials: PP
authors.lastname: Tam
authors.forename: Richard P
authors.initials: RP
authors.lastname: Harvey
mesh_terms: D000818:Animals; D019521:Body Patterning; D019485:Bone Morphogenetic Proteins / Q000378:metabolism*; D002460:Cell Line; D051858:Forkhead Transcription Factors / Q000378:metabolism; D006801:Humans; D008648:Mesoderm / Q000196:embryology / Q000502:physiology*; D051379:Mice; D009154:Mutation; D055457:Nodal Protein / Q000378:metabolism; D015398:Signal Transduction; D051898:Smad1 Protein / Q000235:genetics / Q000378:metabolism*; D051901:Smad4 Protein / Q000235:genetics / Q000378:metabolism*
chemical_list: D019485:Bone Morphogenetic Proteins; D051858:Forkhead Transcription Factors; C491117:Foxh1 protein, mouse; D055457:Nodal Protein; C526008:Nodal protein, mouse; D051898:Smad1 Protein; C497401:Smad1 protein, mouse; D051901:Smad4 Protein; C490810:Smad4 protein, mouse