DLX Genes in the Development and Maintenance of the Vertebrate Skeleton: Implications for Human Pathologies

Abstract

Skeletal shape and mechanical properties define, to a large extent, vertebrate morphology and physical capacities. During development, skeletal morphogenesis results from dynamic communications between chondrocytes, osteoblasts, osteoclasts, and other cellular components of the skeleton. Later in life, skeletal integrity depends on the regulatory cascades that assure the equilibrium between bone formation and resorption. Finally, during aging, skeletal catabolism prevails over anabolism resulting in progressive skeletal degradation. These cellular processes depend on the transcriptional cascades that control cell division and differentiation in each cell type. Most Distal-less (Dlx) homeobox transcription factors are directly involved in determining the proliferation and differentiation of chondrocytes and osteoblasts and, indirectly, of osteoclasts. While the involvement of Dlx genes in the regulation of skeletal formation has been well-analyzed thanks to several mutant mouse models, the role of these genes in the maintenance of bone integrity has been only partially studied. The importance of Dlx genes for adult bone tissues is evidenced by their central role in the regulatory pathways involving Osx/Sp7 and Runx2, the two major master genes of osteogenesis. Dlx genes appear to be involved in several bone pathologies including, for example, osteoporosis. Indeed, at least five large-scale GWAS studies which aimed to detect loci associated with human bone mineral density (BMD) have identified a known DLX5/6 regulatory region within chromosome 7q21.3 in proximity of SEM1/FLJ42280/DSS1 coding sequences, suggesting that DLX5/6 expression is critical in determining healthy BMD. This review aims to summarize the major findings concerning the involvement of Dlx genes in skeletal development and homeostasis and their involvement in skeletal aging and pathology.

A Neanderthal/Denisovan GLI3 variant contributes to anatomical variations in mice

“…A total of 453 and 238 genes were up-or down-regulated in 1540C compared to wild-type mice [|fold change (Fc)|≥1.5, false discovery rate (FDR)<0.05, Table S4]. We found that DEGs included Msx1, Dlx1 and Dlx2, which were known to be essential for skeletal morphology (40,41). Notably, several histone H4 cluster genes, such as H4c2, H4c6 and H4c14 were upregulated in 1540C mice, suggesting that the arginine to cysteine substitution of Gli3 commonly affects specific histone components in mice and humans (Table S4).…”

A Neanderthal/Denisovan GLI3 variant contributes to anatomical variations in mice

“…A total of 453 and 238 genes were upor downregulated in 1540C compared to wild-type mice [|Fc| ≥ 1.5, false discovery rate (FDR) < 0.05, Supplementary Table S4]. We found that DEGs included Msx1, Dlx1 and Dlx2, which were known to be essential for skeletal morphology (Alappat et al, 2003;Levi et al, 2022). Notably, several histone H4 cluster genes, such as H4c2, H4c6 and H4c14 were upregulated in 1540C mice, suggesting that the arginine to cysteine substitution of Gli3 commonly affects Frontiers in Cell and Developmental Biology frontiersin.org specific histone components in mice and humans (Supplementary Table S4).…”

Genetic basis for skeletal new bone formation

“…In these mice, both intramembranous and endochondral ossification were blocked, since osteoblasts were in arrest state and neither osteocalcin (OCN) nor osteopontin (OPN) were expressed [10]. Mice heterozygous for Cbfa1 showed bone defects similar to the human syndrome called cleidocranial dysplasia, a rare condition that effects teeth and bones, such as the face, skull, clavicles, spine, and legs, in which ossification is often absent or deformed [11].…”