Transmembrane protein 88: a Wnt regulatory protein that specifies cardiomyocyte development.
Genetic regulation of the cell fate transition from lateral plate mesoderm to the specification of cardiomyocytes requires suppression of Wnt/β-catenin signaling, but the mechanism for this is not well understood. By analyzing gene expression and chromatin dynamics during directed differentiation of human embryonic stem cells (hESCs), we identified a suppressor of Wnt/β-catenin signaling, transmembrane protein 88 (TMEM88), as a potential regulator of cardiovascular progenitor cell (CVP) specification. During the transition from mesoderm to the CVP, TMEM88 has a chromatin signature of genes that mediate cell fate decisions, and its expression is highly upregulated in advance of key cardiac transcription factors in vitro and in vivo. In early zebrafish embryos, tmem88a is expressed broadly in the lateral plate mesoderm, including the bilateral heart fields. Short hairpin RNA targeting of TMEM88 during hESC cardiac differentiation increases Wnt/β-catenin signaling, confirming its role as a suppressor of this pathway. TMEM88 knockdown has no effect on NKX2.5 or GATA4 expression, but 80% of genes most highly induced during CVP development have reduced expression, suggesting adoption of a new cell fate. In support of this, analysis of later stage cell differentiation showed that TMEM88 knockdown inhibits cardiomyocyte differentiation and promotes endothelial differentiation. Taken together, TMEM88 is crucial for heart development and acts downstream of GATA factors in the pre-cardiac mesoderm to specify lineage commitment of cardiomyocyte development through inhibition of Wnt/β-catenin signaling.
Department of Pathology, University of Washington, Seattle, WA 98195-7470, USA.
Nathan J
NJ
Palpant
Lil
L
Pabon
Jeremy S
JS
Rabinowitz
Brandon K
BK
Hadland
Cristi L
CL
Stoick-Cooper
Sharon L
SL
Paige
Irwin D
ID
Bernstein
Randall T
RT
Moon
Charles E
CE
Murry
D000818:Animals; D019070:Cell Lineage / Q000235:genetics; D015536:Down-Regulation / Q000235:genetics; D004625:Embryo, Nonmammalian / Q000166:cytology / Q000378:metabolism; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D055785:Gene Knockdown Techniques; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008954:Models, Biological; D032383:Myocytes, Cardiac / Q000166:cytology* / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism; D015854:Up-Regulation / Q000235:genetics; D051153:Wnt Proteins / Q000378:metabolism*; D015027:Zebrafish / Q000196:embryology* / Q000235:genetics; D029961:Zebrafish Proteins / Q000235:genetics / Q000378:metabolism*; D051176:beta Catenin / Q000378:metabolism
D008565:Membrane Proteins; C555652:TMEM88 protein, human; C584121:Tmem88a protein, zebrafish; D051153:Wnt Proteins; D029961:Zebrafish Proteins; D051176:beta Catenin
Chromatin; Gene; Heart development; Human embryonic stem cell; Mesoderm; TMEM88; Wnt signaling; Zebrafish