RRC ID 78620
Author Azuma N, Yokoi T, Tanaka T, Matsuzaka E, Saida Y, Nishina S, Terao M, Takada S, Fukami M, Okamura K, Maehara K, Yamasaki T, Hirayama J, Nishina H, Handa H, Yamaguchi Y.
Title Integrator complex subunit 15 controls mRNA splicing and is critical for eye development.
Journal Hum Mol Genet
Abstract The eye and brain are composed of elaborately organized tissues, development of which is supported by spatiotemporally precise expression of a number of transcription factors and developmental regulators. Here we report the molecular and genetic characterization of Integrator complex subunit 15 (INTS15). INTS15 was identified in search for the causative gene(s) for an autosomal-dominant eye disease with variable individual manifestation found in a large pedigree. While homozygous Ints15 knockout mice are embryonic lethal, mutant mice lacking a small C-terminal region of Ints15 show ocular malformations similar to the human patients. INTS15 is highly expressed in the eye and brain during embryogenesis and stably interacts with the Integrator complex to support small nuclear RNA 3' end processing. Its knockdown resulted in missplicing of a large number of genes, probably as a secondary consequence, and substantially affected genes associated with eye and brain development. Moreover, studies using human iPS cells-derived neural progenitor cells showed that INTS15 is critical for axonal outgrowth in retinal ganglion cells. This study suggests a new link between general transcription machinery and a highly specific hereditary disease.
Volume 32(12)
Pages 2032-2045
Published 2023-6-5
DOI 10.1093/hmg/ddad034
PII 7059315
PMID 36851842
MeSH Animals Brain / growth & development Cell Survival Eye* / growth & development Eye Abnormalities* / genetics Female Humans Intracellular Signaling Peptides and Proteins* / genetics Intracellular Signaling Peptides and Proteins* / metabolism Male Mice Mice, Inbred C57BL Mice, Inbred DBA Mice, Knockout Pedigree RNA Processing, Post-Transcriptional RNA, Small Nuclear / metabolism Stem Cells / metabolism
Human and Animal Cells 409B2(HPS0076)