Ciliopathy Protein Tmem107 Plays Multiple Roles in Craniofacial Development

Abstract

A broad spectrum of human diseases called ciliopathies is caused by defective primary cilia morphology or signal transduction. The primary cilium is a solitary organelle that responds to mechanical and chemical stimuli from extracellular and intracellular environments. Transmembrane protein 107 (TMEM107) is localized in the primary cilium and is enriched at the transition zone where it acts to regulate protein content of the cilium. Mutations in TMEM107 were previously connected with oral-facial-digital syndrome, Meckel-Gruber syndrome, and Joubert syndrome exhibiting a range of ciliopathic defects. Here, we analyze a role of Tmem107 in craniofacial development with special focus on palate formation, using mouse embryos with a complete knockout of Tmem107. Tmem107 mice were affected by a broad spectrum of craniofacial defects, including shorter snout, expansion of the facial midline, cleft lip, extensive exencephaly, and microphthalmia or anophthalmia. External abnormalities were accompanied by defects in skeletal structures, including ossification delay in several membranous bones and enlargement of the nasal septum or defects in vomeronasal cartilage. Alteration in palatal shelves growth resulted in clefting of the secondary palate. Palatal defects were caused by increased mesenchymal proliferation leading to early overgrowth of palatal shelves followed by defects in their horizontalization. Moreover, the expression of epithelial stemness marker SOX2 was altered in the palatal shelves of Tmem107 animals, and differences in mesenchymal SOX9 expression demonstrated the enhancement of neural crest migration. Detailed analysis of primary cilia revealed region-specific changes in ciliary morphology accompanied by alteration of acetylated tubulin and IFT88 expression. Moreover, Shh and Gli1 expression was increased in Tmem107 animals as shown by in situ hybridization. Thus, TMEM107 is essential for proper head development, and defective TMEM107 function leads to ciliary morphology disruptions in a region-specific manner, which may explain the complex mutant phenotype.

MicroRNA-124-3p suppresses mouse lip mesenchymal cell proliferation through the regulation of genes associated with cleft lip in the mouse

“…The phenotype was rescued by overexpression of Smad1 ( Ap2a IRESCre / + ;COET;Fsmad1 ).CLO or CLP33 Tfap2a transcription factor AP-2, alpha[42]25381013 Tfap2a null/neo mice show bilateral CL and CP at 100%.CLP34 Tgfbr1 (aka Alk5) transforming growth factor, beta receptor I[43]18586087 Nestin-Cre;Tgfbr1 cKO mice show either unilateral or bilateral CL at 64%. No information about CP.CLO or CLP35 Tmem107 transmembrane protein 107[44, 45]22698544; 28954202Homozygous mutant mice show CL and CP at 14%.CLP36 Trp53 transformation related protein 53[46]25119037 CMV-Cre;Trp53 LSL-25.26.53.54/+ mice show CL and CP.CLP37 Trp63 transformation related protein 63[47]18634775Homozygous null mutant mice show bilateral CL and CP at 100%.CLP38 Wdr19 (aka Ift144) WD repeat domain 19[48]22228095Homozygous mutant mice show bilateral CL and CP. Mutation is ENU-induced single point mutation.CLP39 Wnt9b wingless-type MMTV integration site family, member 9B[49]21982646 Foxg1-Cre /+ ;Wnt9b cKO mice show bilateral CL at 59% and CP.CLO or CLPCLO, cleft lip only; CLP, cleft lip and cleft palate; CPO, cleft palate only…”

Mouse genetics reveals Barttin as a genetic modifier of Joubert syndrome

“…Recently, the mouse has been shown to provide a good model for numerous ciliopathies and these models have begun to elucidate the underlying mechanisms of these diseases (18)(19)(20)(21). Furthermore, there is evidence to suggest that murine ciliopathy phenotypes are influenced by genetic modifiers.…”

TMEM107 inhibits EMT and invasion of NSCLC through regulating the Hedgehog pathway

“…This is consistent with the results of Christopher et al and Cela et al where TMEM107 deletion inhibited differentiation and promoted migration of neuronal stem cells in mouse embryos. 15,16 The invasiveness of NSCLC has been shown to be related to the acquisition of EMT. 9 We found that TMEM107 knockdown made A549 and H460 cells lose Ecadherin and gain N-cadherin and vimentin which are important symbols of occurrence of EMT, 28 suggesting a novel mechanism underlying the involvement of TMEM107 in invasion of NSCLC.…”

“…[12][13][14] TMEM107 is a relatively newly identified gene which encodes for transmembrane protein 107 (TMEM107), which is localized at the transition zone of the primary cilium and regulates the development and protein content of the cilium. [15][16][17][18][19][20] Fibroblasts from patients with mutations in TMEM107 showed a reduced number of cilia, altered cilia length, and impaired Hedgehog signaling in several studies. [17][18][19] Christopher et al and Cela et al confirmed that TMEM107 deletion could cause significant dysfunction of the Hedgehog signaling pathway in mice, which in turn affects the differentiation and migration of their embryonic cells.…”

“…[17][18][19] Christopher et al and Cela et al confirmed that TMEM107 deletion could cause significant dysfunction of the Hedgehog signaling pathway in mice, which in turn affects the differentiation and migration of their embryonic cells. 15,16 Moreover, data from databases indicate that TMEM107 gene expression is lower in lung adenocarcinoma (LUAC) and lung squamous carcinoma (LUSC) than that in normal lung, and lower TMEM107 mRNA expression is associated with poor overall prognosis in the lung cancer population.…”