, 2009, Seo et al., 2009 and Sharma et al., 2008). Mutations in ACIII are associated with obesity in both mice and humans ( Nordman et al., 2008 and Wang et al., 2009b). Direct evidence of an association between cilia dysfunction and obesity comes from deleting Kif3a or Ift88 conditionally in adult mice. Cilia are stunted and animals

overeat, becoming obese. This occurs despite elevated leptin, a satiety signal, suggesting the satiety response is compromised in the absence of functional Protease Inhibitor Library cilia ( Davenport et al., 2007). Ciliated neurons that regulate feeding include a group of pro-opiomelanocortin (POMC)-expressing neurons in the hypothalamic arcuate nucleus. These cells respond to leptin by cleaving POMC to generate α-melanocyte-stimulating hormone (α-MSH), which inhibits feeding, and mice in which Kif3a is selleck screening library deleted selectively from POMC neurons become obese ( Davenport et al., 2007 and Sharma et al., 2008). What ciliary signaling pathways in POMC neurons might modulate α-MSH production, however, remains unclear. The localization of leptin receptors to POMC cell cilia might be predicted, for

example, but has not been confirmed. Connecting Shh signaling with the cilium illuminates CNS defects found in cilliopathic syndromes and other human disease states. Ciliated cerebellar granule neuron precursors (GNPs) proliferate in a Shh-dependent manner in the external granule layer (EGL) of the developing cerebellum (Dahmane and Ruiz i Altaba, 1999, Wallace, 1999 and Wechsler-Reya and Scott, 1999). In mice with conditional deletions of Ift88 or Kif3a, cilia on EGL precursors are stunted, cerebellar granule neurons are fewer, and the cerebellum is hypoplastic, similar to its appearance in Joubert

through Syndrome ( Chizhikov et al., 2007 and Spassky et al., 2008). Learning disabilities are also a feature of several ciliopathies. Although associated defects in the hippocampus have yet to be reported in human patients, the hippocampal dentate gyrus (DG) in mice is highly sensitive to the disruption of primary cilia. DG progenitor cells are ciliated, and respond to Shh to generate granule neurons (Breunig et al., 2008 and Han et al., 2008). Deleting Kif3a in DG progenitor cells stunts primary cilia, decreases Shh signaling in the DG, and inhibits the normal perinatal expansion of DG progenitor population. This reduces the main wave of production of DG neurons in the first three weeks after birth, as well as the initial allocation of radial astrocyte precursors that supply new DG neurons into adulthood ( Han et al., 2008). Similar results are seen in mice deficient in Ift88 ( Han et al., 2008) and in the stumpy mouse mutant, in which ciliogenesis is still more impaired ( Breunig et al., 2008 and Town et al., 2008). The adult neural stem cells of the DG are themselves ciliated, and the role of primary cilia in these cells awaits analysis of mice with deletion of cilia in adulthood.