Increased bone resorption and osteopenia in <i>Dlx5</i> heterozygous mice

Samee, Nadeem; Geoffroy, Valérie; Marty, Caroline; Schiltz, Corinne; Vieux-Rochas, Maxence; Clément-Lacroix, Philippe; Belleville, Cécile; Levi, Giovanni; Vernejoul, Marie‐Christine de

doi:10.1002/jcb.22188

Cited by 13 publications

(11 citation statements)

References 32 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We focused on the two genes with the highest kme (Table 2), melanoma antigen, family D, 1 ( Maged1 ) and par-6 partitioning defective 6 homolog gamma (C. elegans) ( Pard6g ). Maged1 is a transcriptional co-activator that has been implicated in the regulation of myogenic differentiation [30], sexual behavior [31], obesity [31] and the transcriptional function of Dlx5 [32], a positive regulator of osteoblast differentiation and bone mass [33], [34]. Pard6g is a homologue of the Par (partitioning defective) family of proteins that are involved in the regulation of cell polarity.…”

Section: Resultsmentioning

confidence: 99%

Systems Genetic Analysis of Osteoblast-Lineage Cells

et al. 2012

View full text Add to dashboard Cite

The osteoblast-lineage consists of cells at various stages of maturation that are essential for skeletal development, growth, and maintenance. Over the past decade, many of the signaling cascades that regulate this lineage have been elucidated; however, little is known of the networks that coordinate, modulate, and transmit these signals. Here, we identify a gene network specific to the osteoblast-lineage through the reconstruction of a bone co-expression network using microarray profiles collected on 96 Hybrid Mouse Diversity Panel (HMDP) inbred strains. Of the 21 modules that comprised the bone network, module 9 (M9) contained genes that were highly correlated with prototypical osteoblast maker genes and were more highly expressed in osteoblasts relative to other bone cells. In addition, the M9 contained many of the key genes that define the osteoblast-lineage, which together suggested that it was specific to this lineage. To use the M9 to identify novel osteoblast genes and highlight its biological relevance, we knocked-down the expression of its two most connected “hub” genes, Maged1 and Pard6g. Their perturbation altered both osteoblast proliferation and differentiation. Furthermore, we demonstrated the mice deficient in Maged1 had decreased bone mineral density (BMD). It was also discovered that a local expression quantitative trait locus (eQTL) regulating the Wnt signaling antagonist Sfrp1 was a key driver of the M9. We also show that the M9 is associated with BMD in the HMDP and is enriched for genes implicated in the regulation of human BMD through genome-wide association studies. In conclusion, we have identified a physiologically relevant gene network and used it to discover novel genes and regulatory mechanisms involved in the function of osteoblast-lineage cells. Our results highlight the power of harnessing natural genetic variation to generate co-expression networks that can be used to gain insight into the function of specific cell-types.

show abstract

Section: Resultsmentioning

confidence: 99%

Systems Genetic Analysis of Osteoblast-Lineage Cells

et al. 2012

View full text Add to dashboard Cite

show abstract

“…Point mutations located within the homeobox give rise to disease at a higher frequency than mutations located within the rest of the gene and often show a dominant effect due to haploinsufficiency [36]. DLX5 is sensitive to haploinsufficiency because, although Dlx5 +/− mice appear normal, closer investigation indicates that they have a decreased bone mineral density [20], [37]. Mutations within the homeobox may also affect proper structural folding of the protein and DNA binding specificity leading to a mutant phenotype [38].…”

Section: Discussionmentioning

confidence: 99%

A LINE-1 Insertion in DLX6 Is Responsible for Cleft Palate and Mandibular Abnormalities in a Canine Model of Pierre Robin Sequence

et al. 2014

View full text Add to dashboard Cite

Cleft palate (CP) is one of the most commonly occurring craniofacial birth defects in humans. In order to study cleft palate in a naturally occurring model system, we utilized the Nova Scotia Duck Tolling Retriever (NSDTR) dog breed. Micro-computed tomography analysis of CP NSDTR craniofacial structures revealed that these dogs exhibit defects similar to those observed in a recognizable subgroup of humans with CP: Pierre Robin Sequence (PRS). We refer to this phenotype in NSDTRs as CP1. Individuals with PRS have a triad of birth defects: shortened mandible, posteriorly placed tongue, and cleft palate. A genome-wide association study in 14 CP NSDTRs and 72 unaffected NSDTRs identified a significantly associated region on canine chromosome 14 (24.2 Mb–29.3 Mb; praw = 4.64×10−15). Sequencing of two regional candidate homeobox genes in NSDTRs, distal-less homeobox 5 (DLX5) and distal-less homeobox 6 (DLX6), identified a 2.1 kb LINE-1 insertion within DLX6 in CP1 NSDTRs. The LINE-1 insertion is predicted to insert a premature stop codon within the homeodomain of DLX6. This prompted the sequencing of DLX5 and DLX6 in a human cohort with CP, where a missense mutation within the highly conserved DLX5 homeobox of a patient with PRS was identified. This suggests the involvement of DLX5 in the development of PRS. These results demonstrate the power of the canine animal model as a genetically tractable approach to understanding naturally occurring craniofacial birth defects in humans.

show abstract

“…The osteoblast differentiation is mediated by transcription factors, including Dlx5 and Dlx6. Dlx5 is known to have a role in osteoblast/osteoclast couple and as a promotor of osteoblast lineage commitment [1,2]. Thus, Dlx5 is a transcriptional actor of Runx2 [3], a key element of osteoblastic differentiation.…”

Section: Referencesmentioning

confidence: 99%