Dkk2 <i>interacts with</i> Pax9 <i>in palate mesenchyme to pattern and tune osteogenesis</i>

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Abstract

Cleft palate is a common craniofacial disorder involving multiple genetic and environmental predisposing factors. Currently, limited insight exists into the molecular mechanisms regulating osteogenic differentiation and patterning in the palate during embryogenesis. This study utilized the Pax9-deficient mouse genetic model of cleft palate to investigate the role of Pax9 in osteogenic differentiation. Single-nucleus transcriptomics and chromatin accessibility assays validated by whole-transcriptome and single-molecule spatial transcriptomics suggest a relationship between separate Pax9+ and osteogenic populations. Loss of Pax9 resulted in premature osteogenic differentiation and bone maturation. The spatially restricted osteogenic domains in Pax9 ^−/− mice are bounded by Dkk2, which normally interfaces with Pax9 in the mesenchyme. Together, these results confirm a regulatory role for the Wnt pathway in patterning of palatal bone, offering novel insights into the complex nature of developmental signaling and osteodifferentiation in the palate.

SUMMARY STATEMENT

Novel evidence of Wnt-mediated osteogenic differentiation and patterning of palatal bone is presented in a murine cleft palate model. Dkk2 is implicated as a spatial regulator of palate ossification zones, in concert with Pax9.

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Most cited references 37

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Regulation of bone mass by Wnt signaling.

Venkatesh Krishnan, Henry Bryant, Ormond A Macdougald (2006)

Wnt proteins are a family of secreted proteins that regulate many aspects of cell growth, differentiation, function, and death. Considerable progress has been made in our understanding of the molecular links between Wnt signaling and bone development and remodeling since initial reports that mutations in the Wnt coreceptor low-density lipoprotein receptor-related protein 5 (LRP5) are causally linked to alterations in human bone mass. Of the pathways activated by Wnts, it is signaling through the canonical (i.e., Wnt/beta-catenin) pathway that increases bone mass through a number of mechanisms including renewal of stem cells, stimulation of preosteoblast replication, induction of osteoblastogenesis, and inhibition of osteoblast and osteocyte apoptosis. This pathway is an enticing target for developing drugs to battle skeletal diseases as Wnt/beta-catenin signaling is composed of a series of molecular interactions that offer potential places for pharmacological intervention. In considering opportunities for anabolic drug discovery in this area, one must consider multiple factors, including (a) the roles of Wnt signaling for development, remodeling, and pathology of bone; (b) how pharmacological interventions that target this pathway may specifically treat osteoporosis and other aspects of skeletal health; and (c) whether the targets within this pathway are amenable to drug intervention. In this Review we discuss the current understanding of this pathway in terms of bone biology and assess whether targeting this pathway might yield novel therapeutics to treat typical bone disorders.

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Secreted and transmembrane wnt inhibitors and activators.

Cristina-Maria Cruciat, Christof Niehrs (2013)

Signaling by the Wnt family of secreted glycoproteins plays important roles in embryonic development and adult homeostasis. Wnt signaling is modulated by a number of evolutionarily conserved inhibitors and activators. Wnt inhibitors belong to small protein families, including sFRP, Dkk, WIF, Wise/SOST, Cerberus, IGFBP, Shisa, Waif1, APCDD1, and Tiki1. Their common feature is to antagonize Wnt signaling by preventing ligand-receptor interactions or Wnt receptor maturation. Conversely, the Wnt activators, R-spondin and Norrin, promote Wnt signaling by binding to Wnt receptors or releasing a Wnt-inhibitory step. With few exceptions, these antagonists and agonists are not pure Wnt modulators, but also affect additional signaling pathways, such as TGF-β and FGF signaling. Here we discuss their interactions with Wnt ligands and Wnt receptors, their role in developmental processes, as well as their implication in disease.

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Canonical Wnt signaling in differentiated osteoblasts controls osteoclast differentiation.

Andrew McMahon, Hans Clevers, Christine Ahn … (2005)

Inactivation of beta-catenin in mesenchymal progenitors prevents osteoblast differentiation; inactivation of Lrp5, a gene encoding a likely Wnt coreceptor, results in low bone mass (osteopenia) by decreasing bone formation. These observations indicate that Wnt signaling controls osteoblast differentiation and suggest that it may regulate bone formation in differentiated osteoblasts. Here, we study later events and find that stabilization of beta-catenin in differentiated osteoblasts results in high bone mass, while its deletion from differentiated osteoblasts leads to osteopenia. Surprisingly, histological analysis showed that these mutations primarily affect bone resorption rather than bone formation. Cellular and molecular studies showed that beta-catenin together with TCF proteins regulates osteoblast expression of Osteoprotegerin, a major inhibitor of osteoclast differentiation. These findings demonstrate that beta-catenin, and presumably Wnt signaling, promote the ability of differentiated osteoblasts to inhibit osteoclast differentiation; thus, they broaden our knowledge of the functions Wnt proteins have at various stages of skeletogenesis.

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Journal

Journal ID (nlm-ta): bioRxiv

Journal ID (publisher-id): BIORXIV

Title: bioRxiv

Publisher: Cold Spring Harbor Laboratory

Publication date (Electronic): 17 May 2023

Electronic Location Identifier: 2023.05.16.541037

Affiliations

[1 ]Section on Craniofacial Genetic Disorders, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA.

[2 ]Department of Biomedical Engineering, University of Utah, Salt Lake City, UT, USA.

[3 ]School of Dentistry, University of Alberta, Edmonton, AB, CA.

[4 ]University of Connecticut School of Dental Medicine, Farmington, CT, USA.

[5 ]Molecular Genomics Core , Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA.

[6 ]Department of Genetics and Genome Sciences, University of Connecticut School of Medicine, Farmington, CT, USA.

Author notes

[* ] Corresponding author: Rena N. D’Souza, D.D.S., M.S., Ph.D., Director, National Institute of Dental and Craniofacial Research, Chief, Section on Craniofacial Genetic Disorders, Eunice Kennedy Shriver National Institute of Child Health and Human Development, 9000 Rockville Pike, Bethesda, MD, USA 20892, Tel: (713) 398-9100; Rena.D’Souza@ 123456nih.gov

Article

DOI: 10.1101/2023.05.16.541037

PMC ID: 10245699

PubMed ID: 37292772

SO-VID: 65d3fa51-731e-4732-89d0-e7d74bbeac9c

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This work is licensed under a Creative Commons Attribution-NoDerivatives 4.0 International License, which allows reusers to copy and distribute the material in any medium or format in unadapted form only, and only so long as attribution is given to the creator. The license allows for commercial use.

Dkk2 interacts with Pax9 in palate mesenchyme to pattern and tune osteogenesis

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Most cited references 37

Regulation of bone mass by Wnt signaling.

Secreted and transmembrane wnt inhibitors and activators.

Canonical Wnt signaling in differentiated osteoblasts controls osteoclast differentiation.

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