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SOX9 Haploinsufficiency reveals SOX9-Noggin to BMP-SMAD signaling pathway in chondrogenesis

ABSTRACT: SOX9 is well-known for its role in chondrogenesis and gonadogensis. Campomelic Dysplasia (CD) is an example of SOX9 haploinsufficiency-caused rare congenital disease, in which the patients are reported to have skeletal abnormalities. In this study, we created a hiPSC-modeling CD patient and investigated the effect of SOX9 on the regulation of chondrocyte differentiation in BMP-SMAD signaling in vitro. In the CD patient transcriptome, the BMP-SMAD signaling pathway and ribosome-related and chromosome segregation-related gene sets were altered. Upon further experimentation, noggin was found to be significantly upregulated in HT and HM mutants. The overexpression of SOX9 also showed upregulation in SOX9 and COL2A1. . We hope this finding can give a better picture of the dosage-dependent role of SOX9 in chondrogenesis and reveal the manifestation of skeletal dysplasia in CD patients, thereby helping to develop better drugs for these patients.

ORGANISM(S): Homo sapiens

PROVIDER: GSE253431 | GEO | 2025/03/04

REPOSITORIES: GEO

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Project description:Purpose: SOX9Y440X is the most commonly reported SOX9 mutation identified in human patients with Campomelic dysplasia, a dominant semi-lethal skeletal disease characterized by congenital shortening and angulation of long bones (campomelia). To understand how the SOX9Y440X mutant cause the abnormal limb development and compare with previously heterozygous Sox9 null mutant, a mouse model with Sox9Y440X mutation has been generated. The goal of this study is to carry out transcriptome analyses (RNA-seq) of E13.5 limbs collected from Sox9+/IRES-EGFP and Sox9+/Y440X-IRES-EGFP mice. GFP+ and GFP- cells were collected from each genotype by FACS. Comparing transcriptome profiles of cells from these two genotypes aims to reveal how the SOX9Y440X mutant causes abnormal limb development. Method: Forelimbs (FL) and hindlimbs (HL) mRNA profiles of E13.5 Sox9+/IRES-EGFP (WT) and Sox9+/Y440X-IRES-EGFP (CD) mice were generated by sequencing. 4-6 pairs of FL and HL buds were collected separately for each genotype. Limb tissues were then digested into single cells, then EGFP positive and negative cells were collected by FACS for each sample. Total RNA from each sample was prepared using Ambion RNA isolation kit (Cat. AM1580). 100ng of total RNA was used from each sample for RNA-sequencing. cDNA libraries were prepared by TruSeq Stranded mRNA Sample Prep Kit (Illumina). Pair-End sequencing of 101bp was done using HiSeq 1500 Sequencer Model. Data processing: Reads was pre-processed and aligned to the mouse GRCm38 (mm10) reference genome and expression levels were quantified using the nfcore/rnaseq workflow. The count matrix from featureCounts was used in the downstream analyses. The Nextflow pipeline for downstream analysis is available at https://github.com/fuxialexander/sox9. With R library edgeR 3.36.0, read counts were normalized using the ‘TMM’ method. We identified differentially expressed genes between the WT and CD groups in GFP+ or GFP- samples with the ‘glmQLFTest’ function and a Benjamini & Hochberg adjusted P-value cutoff of 0.05. Conclusions: Our study represents the first detailed analysis of mouse foetal limbs transcriptomes between Sox9Y440X mutant and wild type. Our work contributes to gain insight into the molecular signalling pathways affected by SOX9Y440X in vivo.

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SOX9 Haploinsufficiency reveals SOX9-Noggin to BMP-SMAD signaling pathway in chondrogenesis

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