Myo/Nog cell regulation of bone morphogenetic protein signaling in the blastocyst is essential for normal morphogenesis and striated muscle lineage specification

Abstract

Cells that express MyoD mRNA, the G8 antigen and the bone morphogenetic protein (BMP) inhibitor noggin (Nog) are present in the epiblast before gastrulation. Ablation of “Myo/Nog” cells in the blastocyst results in an expansion of canonical BMP signaling and prevents the expression of noggin and follistatin before and after the onset of gastrulation. Once eliminated in the epiblast, they are neither replaced nor compensated for as development progresses. Older embryos lacking Myo/Nog cells exhibit severe axial malformations. Although Wnts and Sonic hedgehog are expressed in ablated embryos, skeletal muscle progenitors expressing Pax3 are missing in the somites. Pax3+ cells do emerge adjacent to Wnt3a+ cells in vitro; however, few undergo skeletal myogenesis. Ablation of Myo/Nog cells also results in ectopically placed cardiac progenitors and cardiomyocytes in the somites. Reintroduction of Myo/Nog cells into the epiblast of ablated embryos restores normal patterns of BMP signaling, morphogenesis and skeletal myogenesis, and inhibits the expression of cardiac markers in the somites. This study demonstrates that Myo/Nog cells are essential regulators of BMP signaling in the early epiblast and are indispensable for normal morphogenesis and striated muscle lineage specification.

Role of Myo/Nog Cells in Neuroprotection: Evidence from the Light Damaged Retina

“…Noggin is released from Myo/Nog cells during development and in adult tissues, including eyes of humans and mice [1, 3, 8, 9, 15, 22]. This release is critical for morphogenesis, eye development and skeletal muscle differentiation [1, 8].…”

“…They were identified by their expression of mRNA for the skeletal muscle specific transcription factor MyoD, the bone morphogenetic protein (BMP) inhibitor Noggin and the cell surface protein recognized by the G8 monoclonal antibody (mAb)[1, 4–7]. During gastrulation, Myo/Nog cells become widely distributed in small numbers throughout the embryo [1, 3, 8]. Depletion of Myo/Nog cells in the blastocyst results in an inhibition of skeletal muscle differentiation, externalization of organs through the body wall and severe malformations of the central nervous system [1, 3, 8].…”

“…During gastrulation, Myo/Nog cells become widely distributed in small numbers throughout the embryo [1, 3, 8]. Depletion of Myo/Nog cells in the blastocyst results in an inhibition of skeletal muscle differentiation, externalization of organs through the body wall and severe malformations of the central nervous system [1, 3, 8]. …”

“…retinal folding) [1, 8]. Ocular and other malformations were prevented or reduced in severity with the addition of Noggin or the reintroduction Myo/Nog cells into the embryo, indicating that Myo/Nog cells’ titration of BMP signalling is essential for normal development [1, 3, 8]. …”

Pluripotent and Multipotent Stem Cells Display Distinct Hypoxic miRNA Expression Profiles

“…Within the miRNAs upregulated by hypoxia in hESC a number have had hypothetical or evidenced targets identified thus far. These include NOG (miR-148b-3p), Jumonji domain containing 3 or JMJD3 (miR-146a-5p), Myocardin or MYOCD (miR-4271, -150-5p, -146a-5p, -524-5p and miR-375) and Transmembrane protein 64 or TMEM64 (miR-548a-3p, -128 and miR-302d-3p) [34–37]. A number of downregulated HRMs have also been described elsewhere where their targets frequently have roles in inhibition of differentiation or the differentiation state.…”