Primary cilia in pancreatic development and disease

Abstract

Primary cilia and their anchoring basal bodies are important regulators of a growing list of signaling pathways. Consequently, dysfunction in proteins associated with these structures results in perturbation of the development and function of a spectrum of tissue and cell types. Here, we review the role of cilia in mediating the development and function of the pancreas. We focus on ciliary regulation of major pathways involved in pancreatic development, including Shh, Wnt, TGF-β, Notch, and fibroblast growth factor. We also discuss pancreatic phenotypes associated with ciliary dysfunction, including pancreatic cysts and defects in glucose homeostasis, and explore the potential role of cilia in such defects.

Keywords: FGF; Notch; Shh; TGF-beta; Wnt; cilia; ciliopathies; development; glucose homeostasis; pancreas; pancreatic cysts.

FIGURE 1

Regulation of pancreatic development by cilia-dependent pathways. A. In early endodermal patterning, Wnt/β-catenin signaling is excluded from the foregut endoderm by foregut expression of antagonists (McLin et al., 2007). The dorsal and ventral pancreatic endoderm of the foregut are subsequently specified by suppression of Shh signaling, as a result of FGF and TGF-β signaling from the notochord (Hebrok et al., 1998) and FGF signaling from the cardiogenic mesenchyme (Deutsch et al., 2001). Expression of the pancreatic progenitor marker Pdx1 is upregulated throughout the pancreatic endoderm, specifying progenitor cells that will contribute to the mature organ. Primary cilia prevent improper activation of both canonical Wnt signaling (Gerdes et al., 2007; Corbit et al., 2008), as well as Shh (Cervantes et al., 2010), and are required for proper TGF-β signaling (Clement et al., 2013), implicating proper ciliary function in the patterning of the gut endoderm and the specification of pancreatic progenitor cells. In addition, FGF signaling regulates the length of primary cilia (Brody et al., 2000; Bonnafe et al., 2004; Urban et al., 2006; Neugebauer et al., 2009), which blocks inappropriate activation of Hh signaling in pancreatic epithelium (Cervantes et al., 2010), suggesting that FGFs may repress Hh in pancreatic endoderm by maintaining cilia. B. The pancreatic epithelium, defined by Pdx1 expression, evaginate to form dorsal and ventral pancreatic buds. Pdx1+ cells that lack Notch signaling transiently express Ngn3 and eventually give rise to endocrine cells. Those that retain Notch signaling express Ptf1a, repress Ngn3 expression, and give rise to exocrine cells (Gu et al., 2002; Herrera et al., 2002; Gu et al., 2003). Notch signaling is maintained by mesenchymal FGFs (Hart et al., 2003; Norgaard et al., 2003; Miralles et al., 2006), which favors exocrine differentiation over endocrine differentiation (Bhushan et al., 2001; Hart et al., 2003; Norgaard et al., 2003; Jacquemin et al., 2006). Canonical Wnt signaling is required for the proliferation of pancreatic progenitor cells (Dessimoz et al., 2005; Murtaugh et al., 2005; Papadopoulou and Edlund, 2005; Heiser et al., 2006; Wells et al., 2007), as well as for the exocrine acinar cells (Murtaugh et al., 2005; Wells et al., 2007). Primary cilia in the pancreas are necessary to preclude overactivation of Notch signaling, and therefore may regulate the balance between endocrine and exocrine fates (Cervantes et al., 2010). TGF-β signaling from the surrounding mesenchyme is also important to drive production of endocrine fates from the pancreatic epithelium and inhibit exocrine fates. In contrast, canonical Wnt signaling is essential for the proliferation of acinar cells and preventing endocrine differentiation. Given the role of cilia in inhibiting Wnt signaling and promoting TGF-β signaling, cilia may block improper Wnt signaling and promote TGF-β in endocrine precursor cells. The absence of cilia in the main exocrine lineage, acinar cells, however, may serve the opposite function, providing an environment conducive to high levels of Wnt/β-catenin signaling. C. During the secondary transition of pancreatic development, tip cells at the termini of ducts give rise to exocrine acinar cells and trunk cells lining the ducts give rise to endocrine and ductal cells. Notch signaling regulates the balance between tip and trunk fates; active Notch promotes trunk identity and represses tip identity, and tip cells expressing low levels of Notch proliferate rapidly under the control of canonical Wnt signaling, ultimately producing acinar cells. Additionally, trunk cells maintain dual potential: high levels of Notch activity lead to the formation of duct cells through repression of Ngn3 and low levels of Notch enhance Ngn3 expression, driving differentiation of endocrine cells (Shih et al., 2012). Primary cilia may regulate these processes by coordinating regulation of Notch.