Itpr1 regulates the formation of anterior eye segment tissues derived from neural crest cells
| Autor: | Akira Kinoshita, Tatsuya Kishino, Ryoichi Mori, Naoko Asahina, Yutaka Negishi, Hideaki Shiraishi, Kana Hosoki, Koh-ichiro Yoshiura, Masahiro Nakashima, Kiyotaka Tomiwa, Katsuya Matsuda, Shinji Saitoh, Hiroyuki Mishima, Naoko Ishihara, Susumu Tanimura, Kaname Ohyama |
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| Rok vydání: | 2021 |
| Předmět: |
Male
Gene isoform Corneal endothelium Adolescent Cerebellar Ataxia Mice Transgenic SOX9 Biology Transfection Gillespie syndrome Mice Young Adult Anterior Eye Segment Intellectual Disability medicine Animals Humans Inositol 1 4 5-Trisphosphate Receptors Protein Isoforms Gene Knock-In Techniques Child Aniridia Molecular Biology Actin Endoplasmic reticulum Infant Neural crest Exons medicine.disease eye diseases Cell biology Mice Inbred C57BL Disease Models Animal HEK293 Cells Neural Crest Child Preschool Mutation NIH 3T3 Cells Female Developmental Biology |
| Zdroj: | Development. 148 |
| ISSN: | 1477-9129 0950-1991 |
| Popis: | Mutations in ITPR1 cause ataxia and aniridia in individuals with Gillespie syndrome (GLSP). However, the pathogenic mechanisms underlying aniridia remain unclear. We identified a de novo GLSP mutation hotspot in the 3′-region of ITPR1 in five individuals with GLSP. Furthermore, RNA-sequencing and immunoblotting revealed an eye-specific transcript of Itpr1, encoding a 218amino acid isoform. This isoform is localized not only in the endoplasmic reticulum, but also in the nuclear and cytoplasmic membranes. Ocular-specific transcription was repressed by SOX9 and induced by MAF in the anterior eye segment (AES) tissues. Mice lacking seven base pairs of the last Itpr1 exon exhibited ataxia and aniridia, in which the iris lymphatic vessels, sphincter and dilator muscles, corneal endothelium and stroma were disrupted, but the neural crest cells persisted after completion of AES formation. Our analyses revealed that the 218-amino acid isoform regulated the directionality of actin fibers and the intensity of focal adhesion. The isoform might control the nuclear entry of transcriptional regulators, such as YAP. It is also possible that ITPR1 regulates both AES differentiation and muscle contraction in the iris. |
| Databáze: | OpenAIRE |
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