u4atac regulates cilium biogenesis through splicing of the minor intron of tmem107l and rfx7b in zebrafish developing brain

A recent study has uncovered how the U4atac protein, which is transcribed into the minor spliceosome component U4atac snRNA, plays a crucial role in the development of the brain. This protein is associated with various health issues such as microcephaly, growth retardation, skeletal dysplasia, and immunodeficiency when it is not functioning properly.

Previous research had already highlighted the significant impact of U4atac deficiency on splicing of U12-type introns, which make up less than 1% of all introns in the human genome.

The team responsible for this research has now found a connection between U4atac and the primary cilium/centrosome complex. They discovered patients with bi-allelic variants of RNU4ATAC, leading to an atypical Joubert syndrome, a type of ciliopathy. However, the exact mechanisms behind this link were not clear. To investigate further, the researchers conducted a transcriptomic analysis of zebrafish models with a U4atac deficiency using morpholino oligonucleotide (MO) techniques.

By comparing their data with that of patients with RNU4ATAC variants, they identified two candidate genes: TMEM107 and RFX7. TMEM107 codes for a structural protein of the cilium transition zone, while RFX7 encodes a transcription factor involved in primary cilium formation. The team then conducted genetic experiments in the zebrafish model, demonstrating that both gene orthologues, tmem107l and rfx7b, work together with u4atac to ensure correct brain development.

In conclusion, this study establishes TMEM107 and RFX7 as key components of the molecular pathway linking U4atac dysfunction to ciliary defects and impaired brain development. This discovery provides new insights into the physiopathology of RNU4ATAC-related disorders and opens up potential therapeutic avenues for these conditions.