Transcriptomic Analysis Highlights Time-specific Embryonic Adaptation of Mice to the Lack of PrP

The physiological function of the PrP remains largely elusive. Its invalidation does not affect mouse survival and induces subtle phenotypes. To potentially assess this conundrum, we first comparatively analyzed the adult brain transcriptome of wild-type mice with that of transgenic mice invalidated at this locus either at the zygotic (Zürich PrP0/0 mice) or adult stages (NFH-Cre-Lox mice). Only subtle differences could be evidenced in the adult brains following microarray and QPCR analyses. When performed at an early adult stage, neuronal Prnp disruption appeared to sequentially induce an oxidative stress response and a nervous system remodeling, but it involved a limited number of only slightly modified genes. In sharp contrast, analysis at early embryonic stages, 7.5 and 8.5 dpc, just after the suspected normal time set of the Prnp locus activation, led to a transient perturbation of the transcriptome involving a larger number of genes and pointing to potential pathways related to the PrP physiological function. Overall, our data suggests an early adaptation of the mouse to the potentially detrimental lack of PrP during embryogenesis while its presence is less influential or redundant at later developmental stages

Congenital microcoria deletion in mouse links Sox21 dysregulation to disease and suggests a role for TGFB2 in glaucoma and myopia.

Congenital microcoria (MCOR) is a rare hereditary developmental defect of the iris dilator muscle frequently associated with high axial myopia and high intraocular pressure (IOP) glaucoma. The condition is caused by submicroscopic rearrangements of chromosome 13q32.1. However, the mechanisms underlying the failure of iris development and the origin of associated features remain elusive. Here, we present a 3D architecture model of the 13q32.1 region, demonstrating that MCOR-related deletions consistently disrupt the boundary between two topologically associating domains (TADs). Deleting the critical MCOR-causing region in mice reveals ectopic Sox21 expression precisely aligning with Dct, each located in one of the two neighbor TADs. This observation is consistent with the TADs' boundary alteration and adoption of Dct regulatory elements by the Sox21 promoter. Additionally, we identify Tgfb2 as a target gene of SOX21 and show TGFΒ2 accumulation in the aqueous humor of an MCOR-affected subject. Accumulation of TGFB2 is recognized for its role in glaucoma and potential impact on axial myopia. Our results highlight the importance of SOX21-TGFB2 signaling in iris development and control of eye growth and IOP. Insights from MCOR studies may provide therapeutic avenues for this condition but also for glaucoma and high myopia conditions, affecting millions of people