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J Dent Res. 2019 Nov;98(12):1367-1375. doi: 10.1177/0022034519872478. Epub 2019 Sep 11.

Requirement of Hyaluronan Synthase-2 in Craniofacial and Palate Development.

Lan Y1,2,3,4, Qin C2,5, Jiang R1,2,3,4.

Author information

1
Division of Plastic Surgery, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
2
Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
3
Departments of Pediatrics and Surgery, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
4
Shriners Hospitals for Children, Cincinnati, OH, USA.
5
The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) & Ministry of Education Key Laboratory of Oral Biomedicine, School & Hospital of Stomatology, Wuhan University, Wuhan, Hubei, China.

Abstract

Cleft palate is a common major birth defect resulting from disruption of palatal shelf growth, elevation, or fusion during fetal palatogenesis. Whereas the molecular mechanism controlling palatal shelf elevation is not well understood, a prevailing hypothesis is that region-specific accumulation of hyaluronan, a predominant extracellular glycosaminoglycan in developing palatal mesenchyme, plays a major role in palatal shelf elevation. However, direct genetic evidence for a requirement of hyaluronan in palate development is still lacking. In this study, we show that Has2, 1 of 3 hyaluronan synthases in mammals, plays a major role in hyaluronan synthesis in the neural crest-derived craniofacial mesenchyme during palatogenesis in mice. We analyzed developmental defects caused by tissue-specific inactivation of Has2 throughout the cranial neural crest lineage or specifically in developing palatal or mandibular mesenchyme, respectively, using Wnt1-Cre, Osr2-Cre, and Hand2-Cre transgenic mice. Inactivation of Has2 either throughout the neural crest lineage or specifically in the developing palatal mesenchyme caused reduced palatal shelf size and increased palatal mesenchyme cell density prior to the time of normal palatal shelf elevation. Whereas both Has2f/f;Wnt1-Cre and Has2f/f;Osr2-Cre mutant mice exhibit cleft palate at complete penetrance, the Has2f/f; Wnt1-Cre fetuses showed dramatically reduced mandible size and complete failure of palatal shelf elevation, whereas Has2f/f;Osr2-Cre fetuses had normal mandibles and delayed palatal shelf elevation. All Has2f/f;Hand2-Cre pups showed reduced mandible size and about 50% of them had cleft palate with disruption of palatal shelf elevation. Results from explant culture assays indicate that disruption of palatal shelf elevation in Has2f/f;Hand2-Cre mutant fetuses resulted from physical obstruction by the malformed mandible and tongue. Together, these data indicate that hyaluronan plays a crucial intrinsic role in palatal shelf expansion and timely reorientation to the horizontal position above the tongue as well as an important role in mandibular morphogenesis that secondarily affects palatal shelf elevation.

KEYWORDS:

Has2; cleft palate; hyaluronic acid; mandible; micrognathia; palatogenesis

PMID:
31509714
PMCID:
PMC6806131
[Available on 2020-11-01]
DOI:
10.1177/0022034519872478

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