SHP2-Deficiency in Chondrocytes Deforms Orofacial Cartilage and Ciliogenesis in Mice.
Congenital orofacial abnormalities are clinically seen in human syndromes with SHP2 germline mutations such as LEOPARD and Noonan syndrome. Recent studies demonstrate that SHP2-deficiency leads to skeletal abnormalities including scoliosis and cartilaginous benign tumor metachondromatosis, suggesting that growth plate cartilage is a key tissue regulated by SHP2. The role and cellular mechanism of SHP2 in the orofacial cartilage, however, remains unknown. Here, we investigated the postnatal craniofacial development by inducible disruption of Shp2 in chondrocytes. Shp2 conditional knockout (cKO) mice displayed severe deformity of the mandibular condyle accompanied by disorganized, expanded cartilage in the trabecular bone region, enhanced type X collagen, and reduced Erk production. Interestingly, the length of primary cilia, an antenna like organelle sensing environmental signaling, was significantly shortened, and the number of primary cilia was reduced in the cKO mice. The expression levels of intraflagellar transports (IFTs), essential molecules in the assembly and function of primary cilia, were significantly decreased. Taken together, lack of Shp2 in orofacial cartilage led to severe defects of ciliogenesis through IFT reduction, resulting in mandibular condyle malformation and cartilaginous expansion. Our study provides new insights into the molecular pathogenesis of SHP2-deficiency in cartilage and helps to understand orofacial and skeletal manifestations seen in patients with SHP2 mutations.
Center for Excellence in Hip Disorders, Texas Scottish Rite Hospital for Children, Dallas, TX, USA.|Department of Orthopaedic Surgery, University of Texas Southwestern Medical Center, Dallas, TX, USA.|Sports Medicine, Tenri University, Tenri, Nara, Japan.
Nobuhiro
N
Kamiya
Department of Pediatrics, The University of Texas Medical School at Houston, Houston, TX, USA.|Department of Histology and Embryology, Harbin Medical University, Harbin, China.
Jingling
J
Shen
Department of Pediatrics, The University of Texas Medical School at Houston, Houston, TX, USA.
Kazuo
K
Noda
Department of Pediatrics, The University of Texas Medical School at Houston, Houston, TX, USA.
Megumi
M
Kitami
Department of Pathology, Division of Biological Sciences, University of California, San Diego, La Jolla, CA, USA.
Gen-Sheng
GS
Feng
Department of Biochemistry, Rush University Medical Center, Chicago, IL, USA.
Di
D
Chen
Department of Pediatrics, The University of Texas Medical School at Houston, Houston, TX, USA.|Graduate Program in Genes and Development, The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, TX, USA.
Yoshihiro
Y
Komatsu
D000818:Animals; D002356:Cartilage; D019070:Cell Lineage; D019902:Chondrocytes / Q000378:metabolism / Q000473:pathology*; D002923:Cilia / Q000473:pathology*; D005145:Face / Q000473:pathology*; D008334:Mandible / Q000002:abnormalities / Q000473:pathology; D018345:Mice, Knockout; D038081:Organogenesis; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11 / Q000172:deficiency* / Q000378:metabolism*
D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; C516725:Ptpn11 protein, mouse
CHONDROCYTE; CILIOGENESIS; CONDYLE; INTRAFLAGELLAR TRANSPORTS; SHP2