PMC3626941-2046-2530-2-1.pdf - Mukhopadhyay and Jackson Cilia 2013 2:1 http/www.ciliajournal.com/content/2/1/1 COMMENTARY Open Access Cilia tubby mice

PMC3626941-2046-2530-2-1.pdf - Mukhopadhyay and Jackson...

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COMMENTARY Open Access Cilia, tubby mice, and obesity Saikat Mukhopadhyay 1,2* and Peter K Jackson 1 Please see related Research article by Li et al., Abstract Primary cilia have been previously linked to the central regulation of satiety. The tubby mouse is characterized by maturity-onset obesity and blindness. A recent paper demonstrates molecular defects in trafficking of ciliary GPCRs in the central neurons of tubby mice, underscoring the role of ciliary signaling in the pathogenesis of this monogenic obesity syndrome. Background Most neurons in the vertebrate nervous system elaborate primary cilia. Historically, neuronal primary cilia were first identified in neuroepithelial progenitor cells project- ing into the neural tube lumen. Later on, they were described to be broadly present both in neurons and glia [1]. The primary cilia function as sensory antennae in a wide variety of cells. Cilia-localized receptors, which in- clude certain G protein-coupled receptors (GPCRs), and their downstream effectors, determine the sensory mo- dality of cells in specific contexts, especially during ver- tebrate photoreception or olfaction and for responding to morphogens, such as Sonic hedgehog (Shh). Although we have come to appreciate the function of the primary cilium in other tissues and organisms, the functional roles of this ubiquitous neuronal organelle in integrating neuroendocrine signals have remained enigmatic. Dis- eases resulting from disruption of primary cilia and the associated basal body complex, called ciliopathies, often have strong neurological components, emphasizing the role of this cellular compartment in neural development [2]. Interestingly, aside from the strong neurodevelop- mental phenotypes, progressive obesity often affects patients with certain ciliopathies such as the Bardet-Biedel Syndrome (BBS) and Alström Syndrome [3]. Notably, conditional knockout of components of the cilia in the mice hypothalamus results in hyperphagia-induced obesity and underscores the role of ciliary signaling in the central regulation of satiety [4]. Thus, it is imperative to achieve a better understanding of the ciliary signaling pathways in central satiety networks, which could lead to novel ways for treating the global obesity pandemic. The tubby mouse was initially identified as a spontan- eous maturity-onset obesity syndrome [5], and positional cloning strategies in the 1990s mapped the causative mutation to a novel gene of unknown function called Tub [6,7]. In nematodes, tub-1 , the canonical Tub homolog was identified in an RNAi screen for fat storage defects [8], and was found to be expressed in the ciliated neurons [9], highlighting the role of neuroendocrine sig- nals in maintenance of systemic fat homeostasis even in these distant evolutionary relatives. Thanks to a recent paper from Sun et al . [10] the tubby mouse can now be added to the growing list of monogenic obesity syn- dromes with a strong ciliary functional component in the central nervous system [3]. The authors demonstrate
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