Modulation of β-Cell Fate and Function by TGFβ Ligands: A Superfamily With Many Powers

Abstract

Hormones, growth factors, and cytokines coordinate metabolism between tissues and within tissues. The transforming growth factor superfamily signaling pathway encompasses members of the TGF , activin, bone morphogenetic protein, Nodal, and growth and differentiation factor subfamilies, in addition to numerous other ligands, receptors, coreceptors, downstream signaling effectors, and regulating molecules. The elaborate multifunctional effects of this superfamily are highly cell-type and context-dependent (1, 2). Many of these ligands are involved in organ specification, patterning, proliferation, and differentiation, including important roles in the pancreas (3, 4). Studies of transgenic and knockout mice highlight the importance of this signaling pathway in islet development (5), and more recent work has also implicated the TGF superfamily in adult -cell function and maturity (6, 7). In this issue of Endocrinology, Boerner and colleagues (8) report a novel role for Nodal, a secreted TGF superfamily member known for its roles in early embryogenesis and its mitogenic signaling through Smad2/3 and Smad4. Detailed studies on the role of Nodal in adult -cells had not been reported. Boerner et al (8) identified Nodel in adult islets and used complementary techniques, including flow cytometry, to demonstrate that Nodal stimulates human pancreatic -cell proliferation. This contrasts with studies employing pancreatic cell lines wherein Nodal was reported to induce apoptosis and inhibit proliferation (9, 10) and highlights the need to perform proliferation studies in nontransformed cells. This novel role of Nodal adds to the numerous roles that this family appears to have on adult pancreatic cells. Here, we will review developments in the field of TGF signaling in islets and emphasize that delineating clear roles of this signaling pathway has been quite challenging. Genetically engineered mouse models have provided insight, as well as confusion, on the roles of TGF family members (Table 1). Life-long global knockouts can provide information on gene function in the whole organism over its entire lifetime. Distinguishing effects of TGF family members on adult -cell physiology from effects on development is not possible without conditional loss-offunction or gain-of-function models, but these are relatively few in number (11–13). Despite these caveats, a picture of multiple effects of TGF signaling on adult -cell homeostasis has begun to emerge. A recurring phenotype manifested in adult mice carrying mutations in various TGF superfamily genes includes decreased -cell mass, impaired glucose tolerance, and in some cases diabetes. Table 1 provides a glimpse of the plethora of effects of this superfamily, and its downstream signaling molecules, on pancreatic islets. Deletion of the negative downstream effector of TGF signaling Smad7 (14) in Pdx1expressing cells decreased hormone-positive cells in late development (5). On the other hand, conditional overexpression of Smad7 in adult Pdx1-expressing cells altered the -cell gene signature and reduced pancreatic insulin production and release, leading to diabetes (11). Furthermore, Smad7 appears to be crucial for beta-cell proliferation after partial pancreatectomy (50). Thus, the same TGF effector can have opposing roles depending on the temporal context. Moreover, the TGF signaling effectors can have opposing roles, given that Smad3 appears to be a negative regulator of insulin secretion and glucose tolerance (13). Taken together, many lines of evidence clearly suggest a role of this signaling pathway in regulating -cell