TGF-beta family signaling in mesenchymal differentiation

Signaling by transforming growth factor-β (TGF-β) family factors affects many distinct differentiation pathways, including those of the hematopoietic and immune cell lineages, epithelial lineages, and hemangioblasts. Similarly, TGF-β family signaling has revealed that it is a major regulatory network that drives lineage selection and differentiation progression in mesenchymal cells. As with other systems, the signaling activity of TGF-β family members correlates with the temporal and spatial regulation of TGF-β family ligand, receptor, and Smad expression, each of which is regulated during mesenchymal cell differentiation. Likewise, the activities of the ligands, receptors, and Smads are also regulated during differentiation. For example, ligand activity is dictated by secreted antagonists or ligand-binding proteins. Receptors are activated through autocrine and paracrine signaling. Smad activity is defined by combinatorial interactions and cross-talk with other signaling pathways, and the Smads then serve to integrate information from a multitude of signaling pathways that direct the expression and activity of each component of the TGF-β signaling pathway. In this way, the TGF-β family receptors and Smads act as cell-intrinsic regulators of mesenchymal differentiation. In this chapter, we discuss the roles of TGF-β family signaling in mesenchymal differentiation. MESENCHYMAL DIFFERENTIATION The mesenchyme consists of loosely associated stellate-shaped cells, which in the trunk and posterior regions of the head derive from mesoderm, and in the face, jaws, and neck, originate from the neural crest (Noden 1986; Couly et al. 1992; Olivera-Martinez et al. 2000; Matsuoka et al. 2005). Neural crest mesenchyme arises from the dorsal edges of the neuroepithelium during...