MLK3 regulates bone development downstream of the faciogenital dysplasia protein FGD1 in mice
Authors
Zou, WeiguoGreenblatt, Matthew B.
Shim, Jae-Hyuck
Kant, Shashi
Zhai, Bo
Lotinun, Sutada
Brady, Nicholas
Hu, Dorothy Zhang
Gygi, Steven P.
Baron, Roland
Davis, Roger J.
Jones, Dallas
Glimcher, Laurie H.
UMass Chan Affiliations
Program in Molecular MedicineDocument Type
Journal ArticlePublication Date
2011-11-01Keywords
AnimalsBone Development
Disease Models, Animal
Dwarfism
Enzyme Activation
Face
Female
Gene Knock-In Techniques
Genetic Diseases, X-Linked
Genitalia, Male
Guanine Nucleotide Exchange Factors
Hand Deformities, Congenital
Heart Defects, Congenital
Humans
MAP Kinase Kinase Kinases
MAP Kinase Signaling System
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Mice, Mutant Strains
*Mutation
Osteoblasts
Proteins
cdc42 GTP-Binding Protein
p38 Mitogen-Activated Protein Kinases
Biochemistry
Cell Biology
Cellular and Molecular Physiology
Developmental Biology
Molecular Biology
Metadata
Show full item recordAbstract
Mutations in human FYVE, RhoGEF, and PH domain-containing 1 (FGD1) cause faciogenital dysplasia (FGDY; also known as Aarskog syndrome), an X-linked disorder that affects multiple skeletal structures. FGD1 encodes a guanine nucleotide exchange factor (GEF) that specifically activates the Rho GTPase CDC42. However, the mechanisms by which mutations in FGD1 affect skeletal development are unknown. Here, we describe what we believe to be a novel signaling pathway in osteoblasts initiated by FGD1 that involves the MAP3K mixed-lineage kinase 3 (MLK3). We observed that MLK3 functions downstream of FGD1 to regulate ERK and p38 MAPK, which in turn phosphorylate and activate the master regulator of osteoblast differentiation, Runx2. Mutations in FGD1 found in individuals with FGDY ablated its ability to activate MLK3. Consistent with our description of this pathway and the phenotype of patients with FGD1 mutations, mice with a targeted deletion of Mlk3 displayed multiple skeletal defects, including dental abnormalities, deficient calvarial mineralization, and reduced bone mass. Furthermore, mice with knockin of a mutant Mlk3 allele that is resistant to activation by FGD1/CDC42 displayed similar skeletal defects, demonstrating that activation of MLK3 specifically by FGD1/CDC42 is important for skeletal mineralization. Thus, our results provide a putative biochemical mechanism for the skeletal defects in human FGDY and suggest that modulating MAPK signaling may benefit these patients.Source
J Clin Invest. 2011 Nov;121(11):4383-92. doi: 10.1172/JCI59041. Epub 2011 Oct 3. Link to article on publisher's siteDOI
10.1172/JCI59041Permanent Link to this Item
http://hdl.handle.net/20.500.14038/28309PubMed ID
21965325Related Resources
Link to Article in PubMedRights
Publisher PDF posted as allowed by the publisher's author rights policy at http://content-assets.jci.org/admin/forms/jcicopyright.pdf
ae974a485f413a2113503eed53cd6c53
10.1172/JCI59041
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