Combined deficiencies ofMsx1andMsx2cause impaired patterning and survival of the cranial neural crest

Abstract

The neural crest is a multipotent, migratory cell population that contributes to a variety of tissues and organs during vertebrate embryogenesis. Here, we focus on the function of Msx1 and Msx2, homeobox genes implicated in several disorders affecting craniofacial development in humans. We show that Msx1/2mutants exhibit profound deficiencies in the development of structures derived from the cranial and cardiac neural crest. These include hypoplastic and mispatterned cranial ganglia, dysmorphogenesis of pharyngeal arch derivatives and abnormal organization of conotruncal structures in the developing heart. The expression of the neural crest markers Ap-2α, Sox10 and cadherin 6 (cdh6) in Msx1/2mutants revealed an apparent retardation in the migration of subpopulations of preotic and postotic neural crest cells, and a disorganization of neural crest cells paralleling patterning defects in cranial nerves. In addition, normally distinct subpopulations of migrating crest underwent mixing. The expression of the hindbrain markers Krox20 and Epha4 was altered in Msx1/2 mutants, suggesting that defects in neural crest populations may result, in part, from defects in rhombomere identity. Msx1/2 mutants also exhibited increased Bmp4expression in migratory cranial neural crest and pharyngeal arches. Finally,proliferation of neural crest-derived mesenchyme was unchanged, but the number of apoptotic cells was increased substantially in neural crest-derived cells that contribute to the cranial ganglia and the first pharyngeal arch. This increase in apoptosis may contribute to the mispatterning of the cranial ganglia and the hypoplasia of the first arch.

Neuropilin 2/semaphorin 3F signaling is essential for cranial neural crest migration and trigeminal ganglion condensation

“…In the head mesenchyme, Twist is required for proper segregation of branchial arch streams 1 and 2 (Soo et al, 2002), while Tbx1 prevents entry of second branchial arch stream crest into the first branchial arch (Moraes et al, 2005). Meanwhile, Msx1 and Msx2 are expressed in the dorsal neural tube and cranial crest, and double mutant mice also display connections between branchial arch streams 1 and 2 (Ishii et al, 2005). Combinatorial Hox gene expression defines rhombomere identity, and the fate the of the resulting crest (Trainor and Krumlauf, 2000a).…”

Recent advances in craniofacial morphogenesis

“…Both Msx1 and Msx2 are expressed in the midline region, and loss of BMP4 signaling results in compromised Msx gene expression. Mutation of Msx1 and Msx2 genes results in midline cleft of the first arch and severe defects in mandibular morphogenesis (Satokata et al, 2000;Ishii et al, 2005;our unpublished data).…”

“…For example, BMP signaling controls Msx gene expression by directly regulating Msx2 promoter activity (Brugger et al, 2004). There is also an apparent feedback for BMP signaling by the Msx genes, because loss of Msx1 and Msx2 results in altered Bmp4 expression in the CNC cells (Ishii et al, 2005). Msx1 and Msx2 function redundantly in regulating the survival and proliferation of CNC cells during craniofacial development.…”

“…Msx1 and Msx2 function redundantly in regulating the survival and proliferation of CNC cells during craniofacial development. This regulation is most likely carried out through the control of cell cycle progression (Hu et al, 2001;Han et al, 2003, Ishii et al, 2005. Recently, studies in Xenopus have shown that a Myc-mediated Id3 expression level is critical for determining whether the neural crest cells will proliferate or die, thus determining the size of the neural crest population (Kee and Bronner-Fraser, 2005;Light et al, 2005).…”

Extensive expression of craniofacial related homeobox genes in canine mammary sarcomas

“…Table 2), e.g., Goosecoid [48], SatB2 [21], MSX1 and MSX2 [49,50], DLX5 and DLX6 [51], paired related homeobox 1 [52] and SIP1/ZEB2 [53]. The cells forming the craniofacial bone are neural crest-derived [44,54] and it is worth noting that neural crest genes have been found to be upregulated in synovial sarcomas [55,56].…”