Neural crest cells require Meis2 for patterning the mandibular arch via the Sonic hedgehog pathway

Abstract

Cranial neural crest cells (cNCCs) originate in the anterior neural tube and populate pharyngeal arches in which they contribute to formation of bone and cartilage. This cell population also provides molecular signals for the development of tissues of non-neural crest origin, such as the tongue muscles, teeth enamel or gland epithelium. Here we show that the transcription factor Meis2 is expressed in the oral region of the first pharyngeal arch (PA1) and later in the tongue primordium. Conditional inactivation of Meis2 in cNCCs resulted in loss of Sonic hedgehog signalling in the oropharyngeal epithelium and impaired patterning of PA1 along the lateral–medial and oral–aboral axis. Failure of molecular specification of PA1, illustrated by altered expression of Hand1/2, Dlx5, Barx1, Gsc and other markers, led to hypoplastic tongue and ectopic ossification of the mandible. Meis2-mutant mice thus display craniofacial defects that are reminiscent of several human syndromes and patients with mutations in the Meis2 gene.

Sonic Hedgehog signaling pathway in gynecological and genitourinary cancer (Review)

“…2 ) ( 92 , 93 ). A myeloid ecotropic insertion site 2 (MEIS2) transcription factor is another molecule that activates the expression of the SHH gene for patterning the mandibular arch during fetal development, as observed by Fabik et al ( 35 ) in a mouse model. The upregulation of MEIS2 was observed in castration-resistant prostate cancer (PC) ( 94 ) and hepatocellular carcinoma, where its isoform MEIS2C activates the Wnt/β-catenin pathway by interacting with the CDC73 molecule ( 95 ).…”

“…Recent research on genomic DNA of patients affected by holoprosencephaly has revealed that eight synonymous single-nucleotide variants in the SHH gene are associated with a reduced level of SHH protein ( 34 ). A recent in vivo study on Cre-modified mice demonstrated that SHH expression was also crucial for proper fetal development of the tongue and mandible ( 35 ). SHH is the most well-known among other hedgehog family proteins, comprising Desert Hedgehog (DHH) and Indian hedgehog (IHH) molecules ( 36 ).…”

The Mandibular and Hyoid Arches—From Molecular Patterning to Shaping Bone and Cartilage

“…The elimination of Meis2 specifically in NCCs results in extensive craniofacial defects [ 78 ]. Furthermore, NC-specific Meis2 embryonic mutants have elevated osteogenesis in the mandibular and hyoid arch at the expense of disrupted tongue development [ 79 ]. Craniofacial defects in the maxillary and mandibular processes of Meis2 -deficient embryos thus reveal the Hox-independent function of Meis2.…”

“…Craniofacial defects in the maxillary and mandibular processes of Meis2 -deficient embryos thus reveal the Hox-independent function of Meis2. Furthermore, altered osteogenesis within the hyoid arch also results in various defects of the hyoid apparatus in Meis2 -deficient embryos [ 78 , 79 ]. The MEIS–PBX–HOX regulatory circuit seems to be evolutionary conserved.…”

“…Elongation of the styloid process or calcification of the stylohyoid ligament above a specific threshold is a medical condition called Eagle’s syndrome. Alongside Hoxa2 and Pbx1 -null mutants, calcification or chondrification of the stylohyoid ligament resembling human Eagle’s syndrome can also be observed in Meis2 and Prrx2 mutants [ 79 , 92 ]. Calcified stylohyoid ligament conspicuously resembles the hyoid apparatus of some nonhuman mammals, in which it may consist of more parts than in humans.…”