Striking phenotypical difference between Ipo8 knock-out mouse models on different genetic backgrounds explored by RNA-sequencing

IPO8 encodes importin-8, a ubiquitously expressed nuclear transport receptor of the importin-² family. Importin-8 translocates cargoes such as proteins and RNAs from the cytosol to the nucleus. We recently identified bi-allelic loss-of-function IPO8 variants as a cause of a syndromic form of thoracic aortic aneurysm (TAA). An Ipo8 knock-out (Ipo8-/-) mouse model on a C57Bl/6N genetic background displayed aortic root and ascending aortic aneurysms from 8 weeks of age onwards. Surprisingly, the identical Ipo8 knock-out mouse on an Sv129 genetic background did not show any aortic aneurysm development.

This project aims to pinpoint the molecular processes promoting aneurysm development in Ipo8-/- C57Bl/6N mice and/or protecting Ipo8-/- Sv129 mice. In the long term, these findings could contribute to the search for novel therapeutic targets.

Ipo8-/- and wild-type (WT) C57Bl/6N and Sv129 mice (N=8 per group) were sacrificed at 16 weeks. The aortic root and ascending aorta were isolated and RNA was extracted to perform bulk RNA-sequencing.

RNA-sequencing data analysis of the four groups pointed out that the largest variation between the groups was due to the genetic background, rather than the mutation itself. Further analysis revealed significant TGF-β superfamily signalling dysregulation in C57Bl/6N as compared to Sv129 Ipo8-/- mice. In particular, we observed a signature of altered BMP signalling in the C57Bl/6N mutants only. While the TGF-β component of the TGF-β superfamily signalling cascade is a well-known contributor to syndromic TAA, relatively little has been reported on dysregulation of BMP signalling.

RNA-sequencing suggests that dysregulated BMP signalling drives TAA development in a C57Bl/6N Ipo8-/- mouse model. While BMP activity has previously been linked to vascular development and homeostasis, its involvement in TAA represents a novel insight into the disease pathogenesis. Moreover, these findings emphasize the critical role of mouse genetic backgrounds in vascular disease modelling.For image description, please refer to the figure legend and surrounding text.