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.

Fig. 1

Morphogenesis of the human upper lip. (A) SEM facial view of a Stage 13 human embryonic head. (B) SEM micrograph of the right nasal pit of a late Stage 15 human embryo. (C) Enlarged detail of the lower nasal pit shown in B. The boundary between the maxillary and lateral nasal processes is clearly marked by the rounded cells at the surface. Rounded cells also appear at the contact site between the medial and lateral nasal processes. (D) Lateral view of a Stage 17 human embryonic head. The maxillary process is puffed laterally and wedges between the medial and lateral nasal processes. (E) SEM micrograph of a Stage 18 human embryonic head (facial view). (F) Enlarged detail view of the left nostril of the embryo shown in E. Arrowhead points to distinct epithelial bridges in the lower part of the slit-shaped nostril, which continue to fuse and reduce the nostril. All panels are from Hinrichsen (1985) (original figure numbers 4, 15, 17, 27, 46, and 52, copyright of Springer-Verlag Berlin Heidelberg 1985), with kind permission of Springer Science and Business Media. fnp, frontonasal prominence; lnp, lateral nasal process; man, mandibular process; max, maxillary process; mnp, medial nasal process. Scale bars in B, C, and D are 100 μm. Scale bar in E and F are 1 mm and 10 μm, respectively.

Fig. 2

Apoptosis plays an important role in breakdown of the epithelial seam during lip fusion. (A) Frontal section of an E11.0 mouse embryo through the telencephalon and the fusing medial and lateral nasal processes. Red signal marks specific anti-active Caspase-3 antibody staining. (B) High magnification view of the fusing epithelial seam between the medial and lateral nasal processes shown in A. Many of the fusing epithelial cells express active Caspase-3 while very few nasal mesenchyme cells and epithelial cells in other regions express active Caspase-3, indicating specific programmed cell death of the fusing epithelial cells. lnp, lateral nasal process; mnp, medial nasal process.

Fig. 3

Selected gene expression patterns in the developing facial primordia of E10.5 mouse embryos. (A) Whole mount in situ hybridization showing specific expression of Bmp4 mRNA (blue/purple staining) in the distal ectoderm of the lateral nasal, medial nasal, maxillary and mandibular processes. (B, C) Msx1 (B) and Msx2 (C) mRNAs are expressed in overlapping patterns in the distal lateral nasal, medial nasal, maxillary and mandibular mesenchyme. (D) Fgf8 mRNA is expressed dynamically in the ectoderm around the nasal pits as well as in the proximal maxillary and mandibular ectoderm. (E) Wnt3 mRNA is expressed in the maxillary and rostral mandibular ectoderm as well as in the distal medial nasal ectoderm. (F) X-gal staining of an E10.5 hemizygous TOPGAL transgenic mouse embryo showing β-galactosidase activity in the distal ectoderm of the lateral nasal, medial nasal, maxillary and mandibular processes. lnp, lateral nasal process; man, mandibular process; max, maxillary process; mnp, medial nasal process.