Multiple postnatal craniofacial anomalies are characterized by conditional loss of polycystic kidney disease 2 (Pkd2)

Abstract

Polycystin 2 (Pkd2), which belongs to the transient receptor potential family, plays a critical role in development. Pkd2 is mainly localized in the primary cilia, which also function as mechanoreceptors in many cells that influence multiple biological processes including Ca(2+) influx, chemical activity and signalling pathways. Mutations in many cilia proteins result in craniofacial abnormalities. Orofacial tissues constantly receive mechanical forces and are known to develop and grow through intricate signalling pathways. Here we investigate the role of Pkd2, whose role remains unclear in craniofacial development and growth. In order to determine the role of Pkd2 in craniofacial development, we located expression in craniofacial tissues and analysed mice with conditional deletion of Pkd2 in neural crest-derived cells, using Wnt1Cre mice. Pkd2 mutants showed many signs of mechanical trauma such as fractured molar roots, distorted incisors, alveolar bone loss and compressed temporomandibular joints, in addition to abnormal skull shapes. Significantly, mutants showed no indication of any of these phenotypes at embryonic stages when heads perceive no significant mechanical stress in utero. The results suggest that Pkd2 is likely to play a critical role in craniofacial growth as a mechanoreceptor. Pkd2 is also identified as one of the genes responsible for autosomal dominant polycystic kidney disease (ADPKD). Since facial anomalies have never been identified in ADPKD patients, we carried out three-dimensional photography of patient faces and analysed these using dense surface modelling. This analysis revealed specific characteristics of ADPKD patient faces, some of which correlated with those of the mutant mice.

Canonical and noncanonical intraflagellar transport regulates craniofacial skeletal development

“…Although it has been widely recognized that primary cilia are projected like antennas and serve as either chemosensory or mechanosensory organelles, their role in CNCCs remains unclear. Because neural crest-specific loss of Pkd2, which encodes a mechanoreceptor in cilia, leads to multiple craniofacial anomalies at postnatal ages, but not in mice embryos (42), one might speculate that primary cilia predominantly function as chemosensors that mediate numerous growth factor signals during embryonic development (36,43,44). Consistent with a previous report analyzing the disruption of IFT20 in kidney development (17), IFT20 was required for the formation of primary cilia in CNC-derived osteogenic cells (Fig.…”

SHP2-Deficiency in Chondrocytes Deforms Orofacial Cartilage and Ciliogenesis in Mice

“…Conditional loss of Pkd2 leads to multiple postnatal craniofacial anomalies, including the compression of temporomandibular joints when heads receive a mechanical stress. (20) We postulated that SHP2 plays important roles in cilia function in chondrocytes, especially when mandibular condyle cartilage aggressively starts receiving mechanical stresses (eg, occlusal force); ie, from juvenile to young adult stages. To investigate the impact of SHP2-deficiency on these stages, we initiated the induction of SHP2 disruption by tamoxifen injection at the time of weaning (ie, 4 weeks postnatally, juvenile) and continued the induction for 5 weeks (ie, until 9 weeks postnatally, young adult).…”

Polycystin-1 interacts with TAZ to stimulate osteoblastogenesis and inhibit adipogenesis

“…Polycystins are also expressed in other tissues (22,23), and several extrarenal functions are being recognized (23,24), including in the skeleton (25,26), where recent evidence shows that the polycystin complex plays an important role in osteoblastogenesis to control bone formation (27)(28)(29). In this regard, osteoblastspecific deletion of Pkd1 or Pkd2 resulted in osteopenia, reduced runt-related transcription factor 2-dependent (Runx2-dependent) osteoblastogenesis, and impaired bone mechanosensing responses to in vivo mechanical loading in mice (30)(31)(32).…”