Common mechanisms in development and disease: BMP signaling in craniofacial development

Abstract

BMP signaling is one of the key pathways regulating craniofacial development. It is involved in the early pattering of the head, the development of cranial neural crest cells, and facial patterning. It regulates development of its mineralized structures, such as cranial bones, maxilla, mandible, palate, and teeth. Targeted mutations in the mouse have been instrumental to delineate the functional involvement of this signaling network in different aspects of craniofacial development. Gene polymorphisms and mutations in BMP pathway genes have been associated with various non-syndromic and syndromic human craniofacial malformations. The identification of intricate cellular interactions and underlying molecular pathways illustrate the importance of local fine-regulation of Bmp signaling to control proliferation, apoptosis, epithelial-mesenchymal interactions, and stem/progenitor differentiation during craniofacial development. Thus, BMP signaling contributes both to shape and functionality of our facial features. BMP signaling also regulates postnatal craniofacial growth and is associated with dental structures life-long. A more detailed understanding of BMP function in growth, homeostasis, and repair of postnatal craniofacial tissues will contribute to our ability to rationally manipulate this signaling network in the context of tissue engineering.

Characterization of new bone morphogenetic protein (Bmp)‐2 regulatory alleles

“…Our analysis of morphological defects found in the embryos showed neural tube and ventral body wall defects to be among the most common defects observed (Figure ). Such ventral and dorsal patterning defects also are prevalent in mice with reduced BMP2 levels (Castranio and Mishina, ; Correia et al, ; Gavrilov and Lacy, ; Graf et al, ; Kanzler et al, ; Ma et al, ; Rivera‐Feliciano and Tabin, ; Ybot‐Gonzalez et al, ; Ying and Zhao, ; Zhang and Bradley, ). Thus, as expected for a true morphogen, too little or too much of this ligand disrupts morphogenesis.…”

“…BMP2‐deficiencies lead to embryo lethality as early as E7.5 to E9 with defects in both extra‐embryonic and embryonic tissues (Ma, Lu, Schwartz, & Martin, ; Singh et al, ; Zhang and Bradley, ). The absence of BMP2 disrupts key morphological processes such as enclosure of the fetus in extra‐embryonic tissues and the positioning of ventral structures such as the gut endoderm and heart (Gavrilov and Lacy, ), heart specification and cardiogenesis (Ma et al, ; Rivera‐Feliciano and Tabin, ; Zhang and Bradley, ), primordial germ cell generation (Ying and Zhao, ), and craniofacial development (Graf, Malik, Hayano, & Mishina, ). BMP signal gradients control the dorsal‐ventral patterning and morphogenesis of the neural tube with BMP2 playing irreplaceable roles in neural plate morphogenesis (Ybot‐Gonzalez et al, ) and cranial neural tube closure and neural crest cell migration (Castranio and Mishina, ; Correia et al, ; Kanzler, Foreman, Labosky, & Mallo, ).…”

Insights into retinoic acid deficiency and the induction of craniofacial malformations and microcephaly in fetal alcohol spectrum disorder

“…Craniofacial abnormalities have been deemed one of the most common classes of human birth defects by the World Health Organization and the cause of 1‐in‐3 of all congenital birth defects (Twigg & Wilkie, ; Shaw, ). Craniofacial malformations can be caused by genetic predispositions such as mutations in Fgf , Shh , and Bmp4 pathways (Graf, Malik, Hayano, & Mishina, ; Twigg et al, ; Twigg & Wilkie, ; Xavier et al, ), by viral infection as seen in Zika infections causing microcephaly (Kumar et al, ; Polonio, de Freitas, Zanluqui, & Peron, ), by malnutrition as seen in folic acid and vitamin A deficiency (VAD) causing cleft palate (Johansen, Lie, Wilcox, Andersen, & Drevon, ; Wilcox et al, ), and by exposure to teratogens, such as ethanol causing FASD (Jones & Smith, ). While the cause of craniofacial malformations might be different, the effect on the developing embryos is the same.…”

Association between a single‐nucleotide polymorphism in the GREM1 gene and non‐syndromic orofacial cleft in the Chinese population

“…Mouse data show that mutations in GREM1 lead to abnormalities of the limbs, lungs, and kidneys . BMP signaling is essential for craniofacial development . BMP4 has been proven to be a candidate gene for NSOC …”