RGD Reference Report - Gene targeting of the transcription factor Mohawk in rats causes heterotopic ossification of Achilles tendon via failed tenogenesis. - Rat Genome Database

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Gene targeting of the transcription factor Mohawk in rats causes heterotopic ossification of Achilles tendon via failed tenogenesis.

Authors: Suzuki, Hidetsugu  Ito, Yoshiaki  Shinohara, Masahiro  Yamashita, Satoshi  Ichinose, Shizuko  Kishida, Akio  Oyaizu, Takuya  Kayama, Tomohiro  Nakamichi, Ryo  Koda, Naoki  Yagishita, Kazuyoshi  Lotz, Martin K  Okawa, Atsushi  Asahara, Hiroshi 
Citation: Suzuki H, etal., Proc Natl Acad Sci U S A. 2016 Jul 12;113(28):7840-5. doi: 10.1073/pnas.1522054113. Epub 2016 Jul 1.
RGD ID: 40924660
Pubmed: PMID:27370800   (View Abstract at PubMed)
PMCID: PMC4948356   (View Article at PubMed Central)
DOI: DOI:10.1073/pnas.1522054113   (Journal Full-text)

Cell-based or pharmacological approaches for promoting tendon repair are currently not available because the molecular mechanisms of tendon development and healing are not well understood. Although analysis of knockout mice provides many critical insights, small animals such as mice have some limitations. In particular, precise physiological examination for mechanical load and the ability to obtain a sufficient number of primary tendon cells for molecular biology studies are challenging using mice. Here, we generated Mohawk (Mkx)(-/-) rats by using CRISPR/Cas9, which showed not only systemic hypoplasia of tendons similar to Mkx(-/-) mice, but also earlier heterotopic ossification of the Achilles tendon compared with Mkx(-/-) mice. Analysis of tendon-derived cells (TDCs) revealed that Mkx deficiency accelerated chondrogenic and osteogenic differentiation, whereas Mkx overexpression suppressed chondrogenic, osteogenic, and adipogenic differentiation. Furthermore, mechanical stretch stimulation of Mkx(-/-) TDCs led to chondrogenic differentiation, whereas the same stimulation in Mkx(+/+) TDCs led to formation of tenocytes. ChIP-seq of Mkx overexpressing TDCs revealed significant peaks in tenogenic-related genes, such as collagen type (Col)1a1 and Col3a1, and chondrogenic differentiation-related genes, such as SRY-box (Sox)5, Sox6, and Sox9 Our results demonstrate that Mkx has a dual role, including accelerating tendon differentiation and preventing chondrogenic/osteogenic differentiation. This molecular network of Mkx provides a basis for tendon physiology and tissue engineering.



RGD Manual Disease Annotations    Click to see Annotation Detail View

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
MKXHumanHeterotopic Ossification  ISOMkx (Rattus norvegicus)compared to WistarRGD 
MkxRatHeterotopic Ossification  IMP compared to WistarRGD 
MkxMouseHeterotopic Ossification  ISOMkx (Rattus norvegicus)compared to WistarRGD 
Mkxem1AsahRatHeterotopic Ossification  IMP compared to WistarRGD 
WI-Mkxem1AsahRatHeterotopic Ossification  IMP compared to WistarRGD 

Gene Ontology Annotations    Click to see Annotation Detail View

Biological Process

  

Phenotype Annotations    Click to see Annotation Detail View

Mammalian Phenotype

Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
MkxRatabnormal gait  IMP compared to WistarRGD 
Mkxem1AsahRatabnormal gait  IMP compared to WistarRGD 
WI-Mkxem1AsahRatabnormal gait  IMP compared to WistarRGD 
MkxRatabnormal tendon collagen fibril morphology  IMP compared to WistarRGD 
Mkxem1AsahRatabnormal tendon collagen fibril morphology  IMP compared to WistarRGD 
WI-Mkxem1AsahRatabnormal tendon collagen fibril morphology  IMP compared to WistarRGD 
MkxRatabnormal tendon morphology  IMP compared to WistarRGD 
Mkxem1AsahRatabnormal tendon morphology  IMP compared to WistarRGD 
WI-Mkxem1AsahRatabnormal tendon morphology  IMP compared to WistarRGD 
MkxRatdecreased tendon stiffness  IMP compared to WistarRGD 
Mkxem1AsahRatdecreased tendon stiffness  IMP compared to WistarRGD 
WI-Mkxem1AsahRatdecreased tendon stiffness  IMP compared to WistarRGD 
MkxRatincreased bone ossification  IMP compared to WistarRGD 
Mkxem1AsahRatincreased bone ossification  IMP compared to WistarRGD 
WI-Mkxem1AsahRatincreased bone ossification  IMP compared to WistarRGD 
MkxRatwavy tail  IMP compared to WistarRGD 
Mkxem1AsahRatwavy tail  IMP compared to WistarRGD 
WI-Mkxem1AsahRatwavy tail  IMP compared to WistarRGD 
Objects Annotated

Genes (Rattus norvegicus)
Mkx  (mohawk homeobox)
Mkxem1Asah  (mohawk homeobox; CRISPR/Cas9 system induced mutant 1, Asah)

Genes (Mus musculus)
Mkx  (mohawk homeobox)

Genes (Homo sapiens)
MKX  (mohawk homeobox)

Strains
WI-Mkxem1Asah  (NA)


Additional Information