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PMID:10742104

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Citation

Satokata, I, Ma, L, Ohshima, H, Bei, M, Woo, I, Nishizawa, K, Maeda, T, Takano, Y, Uchiyama, M, Heaney, S, Peters, H, Tang, Z, Maxson, R and Maas, R (2000) Msx2 deficiency in mice causes pleiotropic defects in bone growth and ectodermal organ formation. Nat. Genet. 24:391-5

Abstract

The composite structure of the mammalian skull, which forms predominantly via intramembranous ossification, requires precise pre- and post-natal growth regulation of individual calvarial elements. Disturbances of this process frequently cause severe clinical manifestations in humans. Enhanced DNA binding by a mutant MSX2 homeodomain results in a gain of function and produces craniosynostosis in humans. Here we show that Msx2-deficient mice have defects of skull ossification and persistent calvarial foramen. This phenotype results from defective proliferation of osteoprogenitors at the osteogenic front during calvarial morphogenesis, and closely resembles that associated with human MSX2 haploinsufficiency in parietal foramina (PFM). Msx2-/- mice also have defects in endochondral bone formation. In the axial and appendicular skeleton, post-natal deficits in Pth/Pthrp receptor (Pthr) signalling and in expression of marker genes for bone differentiation indicate that Msx2 is required for both chondrogenesis and osteogenesis. Consistent with phenotypes associated with PFM, Msx2-mutant mice also display defective tooth, hair follicle and mammary gland development, and seizures, the latter accompanied by abnormal development of the cerebellum. Most Msx2-mutant phenotypes, including calvarial defects, are enhanced by genetic combination with Msx1 loss of function, indicating that Msx gene dosage can modify expression of the PFM phenotype. Our results provide a developmental basis for PFM and demonstrate that Msx2 is essential at multiple sites during organogenesis.

Links

PubMed Online version:10.1038/74231

Keywords

Abnormalities, Multiple/genetics; Abnormalities, Multiple/pathology; Animals; Bone Development/genetics; Bone and Bones/abnormalities; Bone and Bones/pathology; Cartilage/abnormalities; Cartilage/pathology; Cell Differentiation; Cell Division; Cerebellum/abnormalities; Cerebellum/pathology; Chondrocytes/cytology; DNA-Binding Proteins/deficiency; DNA-Binding Proteins/genetics; Ectodermal Dysplasia/genetics; Ectodermal Dysplasia/pathology; Hair Follicle/abnormalities; Hair Follicle/pathology; Homeodomain Proteins; Mammary Glands, Animal/abnormalities; Mammary Glands, Animal/pathology; Mice; Mice, Knockout; Mice, Mutant Strains; Phenotype; Seizures/genetics; Tooth Abnormalities/genetics; Tooth Abnormalities/pathology

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

MOUSE:MSX1

acts_upstream_of_or_within

GO:0061180: mammary gland epithelium development

ECO:0000316: genetic interaction evidence used in manual assertion

MGI:MGI:97169

P

Seeded From UniProt

complete

MOUSE:MSX2

acts_upstream_of_or_within

GO:0002076: osteoblast development

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:1926381

P

  • occurs_in:(EMAPA:35508)

Seeded From UniProt

complete

MOUSE:MSX2

acts_upstream_of_or_within

GO:0002063: chondrocyte development

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:1926381

P

  • occurs_in:(EMAPA:35508)

Seeded From UniProt

complete

MOUSE:MSX2

acts_upstream_of_or_within

GO:0001503: ossification

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:1926381

P

Seeded From UniProt

complete

MOUSE:MSX2

acts_upstream_of_or_within

GO:0003416: endochondral bone growth

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:1926381

P

Seeded From UniProt

complete

MOUSE:MSX2

acts_upstream_of_or_within

GO:0051795: positive regulation of timing of catagen

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:1926381

P

  • regulates_o_occurs_in:(EMAPA:18769)

Seeded From UniProt

complete

MOUSE:MSX2

acts_upstream_of_or_within

GO:0051216: cartilage development

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:1926381

P

Seeded From UniProt

complete

MOUSE:MSX2

acts_upstream_of_or_within

GO:0061180: mammary gland epithelium development

ECO:0000316: genetic interaction evidence used in manual assertion

MGI:MGI:97168

P

Seeded From UniProt

complete

MOUSE:MSX2

acts_upstream_of_or_within

GO:0060444: branching involved in mammary gland duct morphogenesis

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:1926381

P

Seeded From UniProt

complete

MOUSE:MSX2

acts_upstream_of_or_within

GO:0060364: frontal suture morphogenesis

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:1926381

P

Seeded From UniProt

complete

MOUSE:MSX2

acts_upstream_of_or_within

GO:0060346: bone trabecula formation

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:1926381

P

  • results_in_formation_of:(EMAPA:35508)

Seeded From UniProt

complete

MOUSE:MSX2

acts_upstream_of_or_within

GO:0042476: odontogenesis

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:1926381

P

Seeded From UniProt

complete

MOUSE:MSX2

acts_upstream_of_or_within

GO:0070166: enamel mineralization

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:1926381

P

  • occurs_in:(EMAPA:17917)|occurs_in:(EMAPA:17938)

Seeded From UniProt

complete


See also

References

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