title: NK4 antagonizes Tbx1/10 to promote cardiac versus pharyngeal muscle fate in the ascidian second heart field.
abstract: The heart and head muscles share common developmental origins and genetic underpinnings in vertebrates, including humans. Parts of the heart and cranio-facial musculature derive from common mesodermal progenitors that express NKX2-5, ISL1, and TBX1. This ontogenetic kinship is dramatically reflected in the DiGeorge/Cardio-Velo-Facial syndrome (DGS/CVFS), where mutations of TBX1 cause malformations in the pharyngeal apparatus and cardiac outflow tract. Cardiac progenitors of the first heart field (FHF) do not require TBX1 and segregate precociously from common progenitors of the second heart field (SHF) and pharyngeal muscles. However, the cellular and molecular mechanisms that govern heart versus pharyngeal muscle specification within this lineage remain elusive. Here, we harness the simplicity of the ascidian larva to show that, following asymmetric cell division of common progenitors, NK4/NKX2-5 promotes GATAa/GATA4/5/6 expression and cardiac specification in the second heart precursors by antagonizing Tbx1/10-mediated inhibition of GATAa and activation of Collier/Olf/EBF (COE), the determinant of atrial siphon muscle (ASM) specification. Our results uncover essential regulatory connections between the conserved cardio-pharyngeal factor Tbx1/10 and muscle determinant COE, as well as a mutual antagonism between NK4 and Tbx1/10 activities upstream of GATAa and COE. The latter cross-antagonism underlies a fundamental heart versus pharyngeal muscle fate choice that occurs in a conserved lineage of cardio-pharyngeal progenitors. We propose that this basic ontogenetic motif underlies cardiac and pharyngeal muscle development and evolution in chordates.
authors: Department of Biology, New York University, New York, New York, United States of America.
authors: Wei
authors: W
authors: Wang
authors: Florian
authors: F
authors: Razy-Krajka
authors: Eric
authors: E
authors: Siu
authors: Alexandra
authors: A
authors: Ketcham
authors: Lionel
authors: L
authors: Christiaen
mesh_terms: D000818:Animals; D002938:Ciona intestinalis / Q000196:embryology*; D018507:Gene Expression Regulation, Developmental / Q000502:physiology; D006321:Heart / Q000196:embryology*; D018398:Homeodomain Proteins / Q000502:physiology*; D010609:Pharyngeal Muscles / Q000196:embryology*; D013234:Stem Cells / Q000502:physiology; D020825:T-Box Domain Proteins / Q000502:physiology*; D014157:Transcription Factors / Q000502:physiology
chemical_list: D018398:Homeodomain Proteins; D020825:T-Box Domain Proteins; D014157:Transcription Factors