Itpr1 regulates the formation of anterior eye segment tissues derived from neural crest cells

• DOI: 10.1242/dev.188755
• Publication Date: 2021-08-02T09:50:18Z
• Authors: Akira Kinoshita; Kaname Ohyama; Susumu Tanimura; Katsuya Matsuda; Tatsuya Kishino; Yutaka Negishi; Naoko Asahina; Hideaki Shiraishi; Kana Hosoki; Kiyotaka Tomiwa; Naoko Ishihara; Hiroyuki Mishima; Ryoichi Mori; Masahiro Nakashima; Shinji Saitoh; Koh-ichiro Yoshiura
• Keywords: Male; 0301 basic medicine; 0303 health sciences; Adolescent; Cerebellar Ataxia; Infant; Mice, Transgenic; Exons; Mice, Inbred C57BL; Disease Models, Animal; Mice; 03 medical and health sciences; HEK293 Cells; Anterior Eye Segment; Child, Preschool; Intellectual Disability; Animals; Humans; Inositol 1,4,5-Trisphosphate Receptors; Female; Gene Knock-In Techniques; Child; Aniridia

ABSTRACT 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.