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Expression patterns of ciliopathy genes ARL3 and CEP120 reveal roles in multisystem development.

ABSTRACT: Background: Joubert syndrome and related disorders (JSRD) and Jeune syndrome are multisystem ciliopathy disorders with overlapping phenotypes. There are a growing number of genetic causes for these rare syndromes, including the recently described genes ARL3 and CEP120.

Methods: We sought to explore the developmental expression patterns of ARL3 and CEP120 in humans to gain additional understanding of these genetic conditions. We used an RNA in situ detection technique called RNAscope to characterise ARL3 and CEP120 expression patterns in human embryos and foetuses in collaboration with the MRC-Wellcome Trust Human Developmental Biology Resource.

Results: Both ARL3 and CEP120 are expressed in early human brain development, including the cerebellum and in the developing retina and kidney, consistent with the clinical phenotypes seen with pathogenic variants in these genes.

Conclusions: This study provides insights into the potential pathogenesis of JSRD by uncovering the spatial expression of two JSRD-causative genes during normal human development.

SUBMITTER: Powell L

PROVIDER: S-EPMC7727171 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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Expression patterns of ciliopathy genes ARL3 and CEP120 reveal roles in multisystem development.

Powell L L Barroso-Gil M M Clowry G J GJ Devlin L A LA Molinari E E Ramsbottom S A SA Miles C G CG Sayer J A JA

BMC developmental biology 20201209 1

<h4>Background</h4>Joubert syndrome and related disorders (JSRD) and Jeune syndrome are multisystem ciliopathy disorders with overlapping phenotypes. There are a growing number of genetic causes for these rare syndromes, including the recently described genes ARL3 and CEP120.<h4>Methods</h4>We sought to explore the developmental expression patterns of ARL3 and CEP120 in humans to gain additional understanding of these genetic conditions. We used an RNA in situ detection technique called RNAscope ...[more]

PMID: 33297941

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Project description: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.

Dataset Information

Expression patterns of ciliopathy genes ARL3 and CEP120 reveal roles in multisystem development.

Publications

Expression patterns of ciliopathy genes ARL3 and CEP120 reveal roles in multisystem development.

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