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Bénazet, JD, Pignatti, E, Nugent, A, Unal, E, Laurent, F and Zeller, R (2012) Smad4 is required to induce digit ray primordia and to initiate the aggregation and differentiation of chondrogenic progenitors in mouse limb buds. Development 139:4250-60


SMAD4 is an essential mediator of canonical TGFβ/BMP signal transduction and we inactivated Smad4 in mouse limb buds from early stages onward to study its functions in the mesenchyme. While this Smad4 inactivation did not alter the early Sox9 distribution, prefiguring the chondrogenic primordia of the stylopod and zeugopod, it disrupted formation of all Sox9-positive digit ray primordia. Specific inactivation of Smad4 during handplate development pointed to its differential requirement for posterior and anterior digit ray primordia. At the cellular level, Smad4 deficiency blocked the aggregation of Sox9-positive progenitors, thereby preventing chondrogenic differentiation as revealed by absence of collagen type II. The progressive loss of SOX9 due to disrupting digit ray primordia and chondrogenesis was paralleled by alterations in genes marking other lineages. This pointed to a general loss of tissue organization and diversion of mutant cells toward non-specific connective tissue. Conditional inactivation of Bmp2 and Bmp4 indicated that the loss of digit ray primordia and increase in connective tissue were predominantly a consequence of disrupting SMAD4-mediated BMP signal transduction. In summary, our analysis reveals that SMAD4 is required to initiate: (1) formation of the Sox9-positive digit ray primordia; and (2) aggregation and chondrogenic differentiation of all limb skeletal elements.


PubMed Online version:10.1242/dev.084822


Animals; Bone Morphogenetic Protein 2/metabolism; Bone Morphogenetic Protein 4/metabolism; Cell Differentiation/genetics; Cells, Cultured; Chondrogenesis/genetics; Collagen Type II/deficiency; Connective Tissue/metabolism; Extremities/embryology; Fibroblast Growth Factors/metabolism; Gene Expression Regulation, Developmental; Hedgehog Proteins/metabolism; Intercellular Signaling Peptides and Proteins/metabolism; Limb Buds/cytology; Limb Buds/embryology; Limb Buds/metabolism; Mice; SOX9 Transcription Factor/metabolism; Signal Transduction/genetics; Smad4 Protein/genetics; Smad4 Protein/metabolism; Stem Cells



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


GO:0042733: embryonic digit morphogenesis



As shown in figures 1 and 2, inactivation of Smad4 leads to a lack of development in the skeletal portion of embryonic digits.

CACAO 7501



GO:0042733: embryonic digit morphogenesis

ECO:0000315: mutant phenotype evidence used in manual assertion


Seeded From UniProt


See also


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