Overexpression screen of chromosome 21 genes reveals modulators of Sonic hedgehog signaling relevant to Down syndrome

Abstract

Dysregulation of Sonic hedgehog (SHH) signaling may contribute to multiple Down syndrome-associated phenotypes, including cerebellar hypoplasia, congenital heart defects, craniofacial and skeletal dysmorphologies, and Hirschsprung disease. Granule cell precursors isolated from the developing cerebellum of Ts65Dn mice are less responsive to the mitogenic effects of SHH than euploid cells, and a single postnatal dose of the SHH pathway agonist SAG rescues cerebellar morphology and performance on learning and memory tasks in Ts65Dn mice. SAG treatment also normalizes expression levels of OLIG2 in neural progenitor cells derived from human trisomy 21 iPSCs. However, despite evidence that activating SHH signaling can ameliorate some Down syndrome-associated phenotypes, chromosome 21 does not encode any components of the canonical SHH pathway. Here, we screened 163 chromosome 21 cDNAs in a series of SHH-responsive cell lines to identify chromosome 21 genes that modulate SHH signaling. We confirmed overexpression of trisomic candidate genes using RNA-seq in Ts65Dn and TcMAC21 cerebellum. Our study indicates that some chromosome 21 genes, including DYRK1A, upregulate SHH signaling while others, such as HMGN1 and MIS18A, inhibit SHH signaling. Overexpression of genes involved in chromatin structure and mitosis, but not genes previously implicated in ciliogenesis, regulate the SHH pathway. Our data suggest that cerebellar hypoplasia and other phenotypes related to aberrant SHH signaling arise from the net effect of trisomy for multiple chromosome 21 genes rather than the overexpression of a single trisomic gene. Identifying which chromosome 21 genes modulate SHH signaling may suggest new therapeutic avenues for ameliorating Down syndrome phenotypes.

Comparative analysis of craniofacial shape in two mouse models of Down syndrome: Ts65Dn and TcMAC21

“…Our findings suggest that even though TcMAC21 contain more trisomic genes than Ts65Dn, the DS-related craniofacial phenotype of the former is less pronounced than in the latter. A similar result was reported regarding cerebellar hypoplasia in trisomic mouse models, where TcMAC21 mice displayed milder hypoplasia in the cerebellum than Ts65Dn mice (Moyer et al, 2023).…”

“…Moyer et al. (2023) attributed the mild cerebellar hypoplasia in TcMAC21 (and Dp[16]1Yey) mice to the overexpression of some genes that might provide a compensatory effect, buffering size reduction of the cerebellum.…”

“…Moyer et al (2023) attributed the mild cerebellar hypoplasia in TcMAC21(and Dp[16]1Yey) mice to the overexpression of some genes that might provide a compensatory effect, buffering size reduction of the cerebellum.Another factor that might potentially contribute to the more prominent facial morphology of Ts65Dn is the difference in the background of the various DS mouse models. TcMAC21 mice are maintained on a C57BL/6J (B6) × DBA/2 J (D2) genetic background, whereas the Ts65Dn mice used in this study are an intercross on a C57BL/6J × C3H/HeJ background.…”

Distinct expression patterns of Hedgehog signaling components In mouse gustatory system during postnatal tongue development and adult homeostasis

“…In Down’s syndrome patients (74) and mouse models (75), hyperplastic, disorganized and atrophic neuromuscular junctions in the tongue were seen. Recently, it has been shown that chromosome 21 (which causes Down’s syndrome) transcribes genes that can modulate SHH signaling (76). Although the genes that modulate SHH signaling are yet to be investigated, there is a possibility that perturbed HH signaling can lead to lingual muscle disruption in early postnatal stages.…”