RESUMO
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 crucial regulator of tissue fusion, with mouse models lacking GRHL2 function presenting with a fully penetrant open cranial neural tube, 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 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-derived maxillary prominence mesenchyme, indicative of disrupted BMP signalling. Reducing this elevated NOG expression (by generating Grhl2-/-;Nog+/- embryos) results in 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.
Assuntos
Fenda Labial , Fissura Palatina , Defeitos do Tubo Neural , Animais , Camundongos , Proteínas Morfogenéticas Ósseas/metabolismo , Mamíferos/metabolismo , Tubo Neural/metabolismo , Receptores Nogo/metabolismoRESUMO
Grainyhead-like (GRHL) factors are essential, highly conserved transcription factors (TFs) that regulate processes common to both natural cellular behaviours during embryogenesis, and de-regulation of growth and survival pathways in cancer. Serving to drive the transcription, and therefore activation of multiple co-ordinating pathways, the three GRHL family members (GRHL1-3) are a critical conduit for modulating the molecular landscape that guides cellular decision-making processes during proliferation, epithelial-mesenchymal transition (EMT) and migration. Animal models and in vitro approaches harbouring GRHL loss or gain-of-function are key research tools to understanding gene function, which gives confidence that resultant phenotypes and cellular behaviours may be translatable to humans. Critically, identifying and characterising the target genes to which these factors bind is also essential, as they allow us to discover and understand novel genetic pathways that could ultimately be used as targets for disease diagnosis, drug discovery and therapeutic strategies. GRHL1-3 and their transcriptional targets have been shown to drive comparable cellular processes in Drosophila, C. elegans, zebrafish and mice, and have recently also been implicated in the aetiology and/or progression of a number of human congenital disorders and cancers of epithelial origin. In this review, we will summarise the state of knowledge pertaining to the role of the GRHL family target genes in both development and cancer, primarily through understanding the genetic pathways transcriptionally regulated by these factors across disparate disease contexts.