Development of the upper lip: Morphogenetic and molecular mechanisms

Abstract

The vertebrate upper lip forms from initially freely projecting maxillary, medial nasal, and lateral nasal prominences at the rostral and lateral boundaries of the primitive oral cavity. These facial prominences arise during early embryogenesis from ventrally migrating neural crest cells in combination with the head ectoderm and mesoderm and undergo directed growth and expansion around the nasal pits to actively fuse with each other. Initial fusion is between lateral and medial nasal processes and is followed by fusion between maxillary and medial nasal processes. Fusion between these prominences involves active epithelial filopodial and adhering interactions as well as programmed cell death. Slight defects in growth and patterning of the facial mesenchyme or epithelial fusion result in cleft lip with or without cleft palate, the most common and disfiguring craniofacial birth defect. Recent studies of craniofacial development in animal models have identified components of several major signaling pathways, including Bmp, Fgf, Shh, and Wnt signaling, that are critical for proper midfacial morphogenesis and/or lip fusion. There is also accumulating evidence that these signaling pathways cross-regulate genetically as well as crosstalk intracellularly to control cell proliferation and tissue patterning. This review will summarize the current understanding of the basic morphogenetic processes and molecular mechanisms underlying upper lip development and discuss the complex interactions of the various signaling pathways and challenges for understanding cleft lip pathogenesis.

IRF6, RYK, and PAX9 Expression in Facial Tissue of Children with Cleft Palate

“…In theory, failure at any step in the process can lead to clefts (Jiang et al, 2006); abnormal facial tissue development during gestation is the result of interactions between genetic and environmental factors. Lip development precedes palate formation, and therefore improper lip fusion may secondarily affect palate fusion.…”

Orofacial Clefts: A Worldwide Review of the Problem

“…Furthermore, the development of the embryonic face is similar in mice and humans [66]. The development of the upper lip has been well reviewed and presented for use of the CL/P mutants recently [67]. Mouse mutants with disruption in genes such as Gli2, Gli3, Tgf 2, and Hoxa2 result in CL/P through disturbance to cranial neural crest (CNC) migration and differentiation [68][69][70].…”

Hand1 phosphoregulation within the distal arch neural crest is essential for craniofacial morphogenesis

“…Well-integrated signaling programs function through transcription factors to define tissue patterning and NCC differentiation. The complex signals that govern craniofacial morphogenesis involve a number of input pathways, including Fgf, Shh, Wnt, Bmp, Pdgf, retinoic acid (RA) and endothelin signaling (Abe et al, 2008;Abzhanov and Tabin, 2004;Clouthier et al, 2003;Jiang et al, 2006;Kurihara et al, 1995;Macatee et al, 2003). Dysregulation of NCC migration, proliferation and patterning can result in craniofacial abnormalities observed in numerous human syndromes (Chai and Maxson, 2006;Jiang et al, 2006;Noden and Trainor, 2005;Clouthier et al, 2013).…”