Grainyhead-like 2 (Grhl2) interacts with Noggin to regulate tissue fusion in mouse.

Defective tissue fusion during mammalian embryogenesis results in congenital anomalies such as exencephaly, spina bifida and cleft lip and/or palate. The highly-conserved transcription factor Grainyhead-like 2 (Grhl2) is a critical regulator of tissue fusion, with mouse models lacking Grhl2 function presenting with a fully-penetrant open cranial neural tube (NT), facial and abdominal clefting (abdominoschisis) and an open posterior neuropore. Here we show that Grhl2 interacts with the soluble morphogen-protein and Bone Morphogenetic Protein (BMP) inhibitor Noggin (NOG) to impact tissue fusion during development. The maxillary prominence (MXP) epithelium in embryos lacking Grhl2 shows substantial morphological abnormalities and significant upregulation of NOG expression, together with aberrantly distributed pSMAD5-positive cells within the neural crest cell (NCC)-derived MXP mesenchyme indicative of disrupted BMP-signalling. Reducing this elevated Noggin expression (through generating Grhl2-/-;Noggin+/- embryos) shows delayed embryonic lethality, partial tissue fusion rescue, and restoration of tissue form within the craniofacial epithelia. These data suggest that aberrant epithelial maintenance, partially regulated by Noggin-mediated regulation of BMP-Smad pathways, may underpin tissue fusion defects in Grhl2-/- mice.