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Levi, G.;  Narboux-Nême, N.;  Cohen-Solal, M. Dlx Genes in Skeletal Development and Maintenance. Encyclopedia. Available online: https://encyclopedia.pub/entry/33148 (accessed on 08 May 2024).
Levi G,  Narboux-Nême N,  Cohen-Solal M. Dlx Genes in Skeletal Development and Maintenance. Encyclopedia. Available at: https://encyclopedia.pub/entry/33148. Accessed May 08, 2024.
Levi, Giovanni, Nicolas Narboux-Nême, Martine Cohen-Solal. "Dlx Genes in Skeletal Development and Maintenance" Encyclopedia, https://encyclopedia.pub/entry/33148 (accessed May 08, 2024).
Levi, G.,  Narboux-Nême, N., & Cohen-Solal, M. (2022, November 06). Dlx Genes in Skeletal Development and Maintenance. In Encyclopedia. https://encyclopedia.pub/entry/33148
Levi, Giovanni, et al. "Dlx Genes in Skeletal Development and Maintenance." Encyclopedia. Web. 06 November, 2022.
Dlx Genes in Skeletal Development and Maintenance
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This entry is adapted from the peer-reviewed paper 10.3390/cells11203277

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 from 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. The role of these genes in the maintenance of bone integrity has been only partially studied. Dlx genes appear to be involved in several bone pathologies including, for example, osteoporosis. Indeed, at least five large-scale GWAS studies aimed to detect loci associated to 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. 

Dlx genes skeleton bone osteoblasts osteoclasts homeobox genes

1. The Distal-less gene family in vertebrates

The Distal-less (Dll) gene of Drosophila encodes a homeodomain protein that is one of the first to be expressed during leg primordia and cephalic development [1][2][3]. Adult Dll Drosophila mutants present reduction and dysmorphogenesis of distal segments of most appendages including legs, antennae and mouth parts, indicating that the Dll activity is required for appendage proximo-distal (PD) organization during early larval stages [1][4][5]. In vertebrates, Dlx genes share a homeodomain, homologous to that of Drosophila Dll. During evolution, a linked pair of Dlx genes was generated through ancestral tandem duplication after the divergence of chordates and arthropods but prior to that of vertebrates. This bigenic Dlx cluster was then duplicated twice at the same time as the two genomic duplications that led to the four Hox clusters of existing vertebrates. Finally, the pair of Dlx genes linked to the HoxC cluster was lost in mammals [6][7]. Therefore, the present mammalian genome include six Dlx genes linked in three bigenic pairs, in a tandem convergent configuration facing each other through the 3’ end: Dlx1/Dlx2; Dlx3/Dlx4 (the latter previously named Dlx7) and Dlx5/Dlx6 [3]. 

2. Dlx genes in skeletal morphogenesis, differentiation and remodelling

During early development Dlx genes are expressed by Cranial Neural Crest Cells (CNCCs), but not by mesodermal precursors or by postmigratory Neural Crest Cells of the trunk, Accordingly, Dlx genes play a major morphogenetic role on craniofacial bones while Hox genes determine the identity and shape of axial and appendicular bones. These early morphogenetic functions of Dlx genes are the result of highly dynamic exchanges of regulatory signals between the different cellular components of the developing embryo [8]. Later in development, Dlx2, Dlx3, Dlx5 and Dlx6 assume new functions in different organs; in particular in the post-natal skeleton these genes are involved in the control chondrogenesis and osteogenesis.

Starting at mid gestation, Dlx2, Dlx3, Dlx5 and Dlx6 are expressed in most sites of cartilage condensation and in differentiating osteoblasts in areas of bone formation [9][10][11][12]. The expression of Dlx genes persists then throughout life both in precursor Bone Marrow Mesenchymal Stem Cells (BM-MSCs) and in differentiated chondrocytes and osteoblasts suggesting their involvement in bone remodelling.

The adult skeleton, and bone in particular, is continuously self-regenerating through a process called bone remodelling [13][14]. It has been estimated that in humans most skeletal elements are renewed each decade thanks to the proliferation and differentiation of undifferentiated progenitor cells [14]. Although remodelling is similar for all bones, one should remember that the axial and appendicular skeleton has a different embryonic origin than that of the head: The cephalic skeleton derives exclusively from post-migratory cranial neural crest cells (CNCCs), whereas the rest of the skeleton derives from mesodermal precursors [15][16]. CNCCs-derived tissues of the head do not express Hox genes while axial skeletal elements are Hox-positive. Remarkably, progenitor cells assuring bone remodelling maintain the Hox positive/negative identity of their original tissue even in the adult [17]. Apparently, therefore, there are distinct sub-populations of cephalic and axial skeletal stem cells.

3. Dlx genes in cartilage development and maintenance.

Most Dlx genes are involved in cartilage formation and maintenance and play multiple roles in the recruitment of multipotent mesenchymal cells to the chondrogenic lineage and in their subsequent maturation to chondrocytes.

In particular, Dlx5 and Dlx6, are expressed during chondrogenesis in mouse and avian embryos. Dlx5 is strongly expressed by condensing limb mesenchyme early during limb bud development [9][18][19][20][21]. In early chick and mouse embryos (up to E12.5 for the mouse), the expression of Dlx5 overlaps that of Sox9 and type II collagen [21][22], suggesting that Dlx5 is an early marker of limb mesenchyme differentiation towards the chondrogenic lineage. Later, during axial chondrogenic condensation, the expression of Dlx5/6 does not parallel that of Sox9. Starting at E13.5, Dlx5 is expressed in the mouse growth-plate in proliferating chondrocytes and in Indian hedgehog (Ihh)-positive pre-hypertrophic chondrocytes. At E14.5, Dlx5 is still expressed in the prehypertrophic zone and continues to be expressed in flattened chondrocytes and in the hypertrophic cartilage zone, even where Ihh is downregulated. Dlx5 is also strongly expressed in the perichondrium and in the growth plate cartilage–bone interface. Later, Dlx5 expression persists in proliferating chondrocytes and many Dlx5-positive cells are present in the prehypertrophic zone .
Comparison of Dlx5+/+ and Dlx5−/− E18.5 growth plates shows that, in the absence of the gene, the proliferating zone is significantly larger while the hypertrophic zone is narrower. These data suggest that Dlx5 acts as a regulator of chondrocyte differentiation and has a smaller effect on the control of proliferation [22].
Several in vitro experiments suggest that Dlx5 is an important regulator of multipotent mesenchymal cell recruitment to the chondroblastic lineage and plays a role in chondrocyte maturation. Dlx5 has an anti-proliferative effect on chondrocytes and fibroblasts. Micro-mass assays using chicken embryo limb bud mesenchyme infected with RCAS-Dlx5 show an increased chondrogenic differentiation compared to a non-recombinant RCAS-infected mesenchyme. It appears, therefore, that Dlx5 regulates the progressive transition of immature proliferating chondrocytes to pre-hypertrophic and hypertrophic chondrocytes, confirming the notion that Dlx5 acts as a positive regulator of chondrogenic differentiation. n Dlx5/6−/− embryos, Col2a1 and Col10a1, markers of pre-hypertrophic and hypertrophic chondrocytes, respectively, were still expressed in articular sections, whereas in Dlx5/6+/− embryos, both genes had already been significantly downregulated indicating a severe delay in cartilage differentiation. Both the Fgf/Fgfr3 and the Ihh/Pthrp/Pthrp-R signaling pathways are important for the regulation of chondrocyte proliferation and differentiation, and for the coupling of chondrogenesis to osteogenesis during endochondral ossification . In line with what has been observed for Col2a1 and Col10a1, there is a delay in Fgfr3 and Ihh expression in Dlx5/6−/− developing cartilages, resulting in contrasting patterns of Fgfr3 and Ihh expression in control and Dlx5/6−/− embryos, while Pthrp-R expression is unaffected . Therefore, the expression of most key regulators for chondrogenesis is severely delayed in Dlx5/6−/− developing skeletons, resulting in a severe disruption in the differentiation of chondrocytes to Runx2-expressing cells  [23].

4. Roles of Dlx genes in osteoblast differentiation 

Dlx3

During endochondral ossification Dlx3 is expressed in cells of the osteoblastic lineage and in the inner layer of the periosteum. In E15.5 mouse embryos, Dlx3 is present in osteoblast progenitors, in osteoblasts lining bone trabeculae and in osteocytes at early stages of differentiation, whereas mature osteocytes do not express this gene. At E16.5, Dlx3 is still expressed by cells surrounding the trabeculae and by endosteal osteoblasts of the diaphyseal cortical bone [24].

Overexpression of Dlx3 in MC3T3-E1 cells induced an increased expression of the osteoblast-specific genes Collagen type1, Bone sialo protein, Osteopontin and Osteocalcin. ChIP analysis provided evidence of direct binding of Dlx3 onto the osteocalcin regulatory region [24].

The tricho-dento osseous syndrome (TDO) is an autosomal dominant disorder characterized by enamel hypoplasia, severe taurodontism, moderately increased trabecular bone mineral density and typical kinky/curly hairs. TDO is linked to chromosome 17q21 markers with no indication of genetic heterogeneity [25][26]. The TDO locus has been mapped to the chromosomal region that includes the DLX3-4 tandem and, more specifically to a 4bp deletion in the human DLX3 gene (DLX3 4bp DEL, NT3198 mutation; OMIM 600525) [27][28][29]. Beside taurodontism and enamel hypoplasia, TDO patients carrying this 4bp deletion often present significantly higher bone mineral density in radius, ulna, spines and hips compared to unaffected family members [30]. The 4 bp DLX3 deletion results in a frameshift that changes the last 97 C-terminal amino acids and gives rise to a novel 119 amino acid C-terminal peptide in the mouse Dlx3 cDNA, just 3′ to the homeobox. The homeodomain region in both human and mouse DLX3 genes includes a nuclear localization signal (NLS) [31]. The 4 bp DLX3 deletion does not alter the structure of the homeobox nor of the NLS regions therefore the nuclear translocation ability of mutant DLX3 protein is unchanged.

The trabecular bone volume and the mineral density of mice carrying the Dlx3 4bp deletion is increased both in young and adult individuals. As the rate of bone formation does not increase in vivo in these mice, their phenotype was suggested to derive from decreased osteoclast formation and bone resorption due to the increased serum levels of IFN-γ [32].

The notion that Dlx3 regulates osteoblast activity is reinforced by the fact that Dlx3-deleted bone marrow stroma cells (BMSCs), also show increased osteoblastic differentiation with increased expression of Runx2 and Dlx5. Collectively, these observations suggest that DLX3 is a negative regulator of osteoblastogenesis. This notion is further supported by ChIP analysis on BMSCs, which shows that DLX3 binds to the promoters of Sp7, Dlx5 and Dlx6, and Runx2, directly modulating their activity (see also [33]).

Dlx5 and Dlx6

Dlx5 is expressed by osteoblasts from very early stages of bone development [9][19][34] and persists in these cells throughout life [35]. In perinatal and post-natal bone, Dlx5 expression is predominantly found at the periphery of diaphyseal bone and in cells surrounded by osteoid within the trabeculae [12][36].

Dlx5-/- mice die at birth. Histopathological analysis of their long bones performed in late embryos showed that both trabecular and cortical bone components were affected. By E15.5, Dlx5-/- mice present a significant reduction in the ossified portion of long bones. At birth, histological analysis revealed a lesion characterised by the presence of a more complex structure of the endosteal component of the diaphysis, which forms an elaborate mesh of woven bone, and by the reduction of the periosteal bone lamina [12]. Delayed ossification of the parietal, interparietal and superoccipital bones of Dlx5-/- mice results in open fontanellae. These morphological findings, both in endochondral and intramembranous bone types, suggest that the absence of Dlx5 results in a generalized defect in osteogenesis.

Indeed, the in vitro analysis of Dlx5−/− cells suggests that this transcription factor promotes osteoblast proliferation and differentiation as indicated by the decreased expression of bone differentiation markers and their reduced capacity to generate mineralized nodules in vitro [36]. These Dlx5−/− osteoblastic defects may depend from Runx2 dependent or independent pathways. As will be better discussed later, Dlx5 acts as a transcriptional activator of Runx2 in bone by binding to its P1 promoter [37] and to a Runx2 bone specific enhancer; consequently, Dlx5 inactivation results in decreased Runx2 expression. Dlx5 can also activate osteoblast-specific genes such as ALP and osteocalcin in the absence of Runx2, suggesting a Runx2-independent pathway. Osx expression is also reduced in cultured Dlx5−/− osteoblast, possibly through a Dlx5-dependent/Runx2-independent mechanism [38]. Both osteocalcin and BSP, markers of osteoblast differentiation, are drastically down-regulated in Dlx5−/− osteoblasts, as predicted by the analysis of their regulatory regions and by in vitro studies [34][39]. Remarkably, no significant difference in trabecular thickness, an indicative parameter of osteoblastic activity, was observed in Dlx5−/− mice at birth. This apparent contradiction may depend on the different origin of cortical and trabecular osteoblasts precursors. Indeed, cultured calvaria-derived cells are more similar to cortical than to trabecular osteoblasts from long bones [36].

Simultaneous inactivation of Dlx5 and Dlx6 results in more pronounced abnormalities of endochondral bones than the single inactivation of Dlx5, suggesting a redundant function for the two genes. Serial skeletal sections showed the presence of vascularization and mineralized bone matrix in heterozygous Dlx5/6+/- embryos, while, comparable regions in Dlx5/6-/- embryos consisted of hypertrophic and calcified chondrocytes, with minimal vascular invasion, and a predominantly cartilaginous matrix. Molecular analysis of comparable E16.5 Dlx5/6-/- embryos also suggested a delay in the onset of the osteogenic pathway. Similar Runx2 expression patterns were observed within the chondrium and perichondrium of Dlx5/6+/- and Dlx5/6-/- mice, while osteocalcin gene expression was dramatically reduced in Dlx5/6-/- skeletal sections. Altogether, these results suggest that Dlx5/6 have a partially redundant positive role in the osteoblast maturation pathway, and that, in their absence, the accumulation of mature osteoblasts is severely retarded or absent [23].

5. Association between DLX5/6 and human bone mineral density

DLX5/6 are associated to a type of human ectrodactyly known as Split Hand Foot Malformation Type I (SHFM1) [40]. The inactivation of Dlx5/6 in the mouse results in a similar limb phenotype reinforcing the notion that these genes are responsible for this disease [23][41]. The characterization of DLX5/6 regulatory region performed by generating reporter transgenic animals has permitted to identify 26 tissue-specific enhancers (eDlx#XX) [42] capable to direct the expression of the genes either in the limb, in craniofacial regions and/or in the brain during development. However, the role of these enhancers in the adult is unknown.

Remarkably, at least 5 GWAS studies have found a strong association between adult bone mineral density and SNPs located in the 7q21.3 region that includes eDlx#18 [43][44][45][46][47]. Furthermore, an haplotype controlling bone mineral density and osteoporosis susceptibility has been reported in this locus [48]. This haplotype is constituted by a succession of co-segregating SNPs located in intronic regions close to the gene SEM1/FLJ4220/DSS1 that is associated to SHFM1 but has no known function; this locus includes upstream enhancers of DLX5/6. Collectively, these observations suggest that polymorphisms in SNPs regulating DLX5/6 expression are involved in bone mineral density (BMD) determination and might be considered susceptibility factors for osteoporosis.

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Subjects: Cell Biology
Contributors MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to https://encyclopedia.pub/register :
Giovanni Levi
,
Nicolas Narboux-Nême
,
Martine Cohen-Solal
View Times: 387
Revisions: 3 times (View History)
Update Date: 08 Nov 2022
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