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Abstract

Primary cilia in neurons have often been regarded as rare, vestigial curiosities. However, neuronal cilia are now gaining recognition as ubiquitous organelles in the mammalian brain, raising speculation about what their functions may be. They might have some features tailored for the nervous system and others that serve needs shared by a spectrum of other cell types. Here we review clues from the literature and present new data supporting several possibilities for the significance of neuronal cilia. Our immunocytochemical results show regional heterogeneity in neuronal cilia. Brain regions nearer to the cerebral ventricles had longer cilia, suggesting that they might sense chemicals such as peptides, originating from cerebrospinal fluid. In mutant Tg737^orpkmice, most brain regions appeared to be missing cilia. The importance of intraflagellar transport proteins establishes a functional link between neuronal cilia and other primary cilia.

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Keywords: Neuron, Brain, Cilium, Intraflagellar transport, sst3.

^*Corresponding author. Tel.: +1-940-565-4994; fax: +1-940-565-4136

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1 The long history of the discovery of neuronal cilia

Most neuroscientists would be surprised—if not downright skeptical—to hear that primary cilia are a consistent feature of neurons in the mammalian central nervous system. Over a century ago, the preeminent neuroanatomist Ramón y Cajal (Ramón y Cajal, 1995) drew and described in meticulous detail a myriad of neurons without including primary cilia, so how could neurons have them? To this day, cilia are rarely catalogued among the organelles of neurons, despite several demonstrations of their presence in brain, over a period of decades. In this review, “neuronal cilia” refers to solitary cilia—one per neuron—with the hallmark 9+0 circle of microtubule doublets forming the backbone of the ciliary axoneme. This article highlights what is known about primary cilia in the mammalian central nervous system, but it should be pointed out that primary cilia have been described in neurons of the other vertebrate classes, and in peripheral neurons and glia (Del Cerro and Snider, 1967; Grillo and Palay, 1963; Milhaud and Pappas, 1968; Taxi, 1961). In searching for clues to functions neuronal cilia might have, our scope is not limited by cell type or phylogenetic category.

Some ultrastructural studies reported that neuronal cilia are infrequent, for example, in cat spinal cord (Duncan et al., 1963), guinea pig and human retinal ganglion cells (Allen, 1965), rat lateral geniculatenucleus (Karlsson, 1966), and rat ventral tegmental area (Bayer and Pickel, 1990). Because only a small percentage of electron micrographic sections show primary cilia, it is difficult to appreciate their prevalence without systematic, labor-intensive efforts. Nevertheless, neuronal cilia were recognized as common ultrastructural features of granule cells in rat dentate gyrus(Dahl, 1963), major neuron types in rat cerebellum(Del Cerro and Snider, 1967, 1969), immature rat supraoptic nucleus (Lafarga et al., 1980), guinea pig cerebellum, hypothalamus and neocortex (Vigh-Teichmann et al., 1980), some (but not all) types of retinal neurons in cat and rabbit (Boycott and Hopkins, 1984), hamster paraventricular hypothalamic nucleus (Suarez et al., 1985), human neocortex (Mandl and Megele, 1989), and neuropeptide-containing neurons of rat striatum (Wolfrum and Nitsch, 1992). Even as evidence accumulated that neuronal cilia are standard in various species and brain regions, the impression persisted that neuronal cilia in mammals are probably regressive, vestigial, or of otherwise dubious functional consequence (Bayer and Pickel, 1990; Dahl, 1963; Duncan et al., 1963; Peters et al., 1976; Ruelaet al., 1981). This impression was apparently fueled by fragmentary evidence that primary cilia are more characteristic of earlier phylogeny and ontogeny, the belief that lack of the central microtubule pair diagnostic of motile cilia indicates regressive loss of function, and the absence of information about functions of primary cilia.

Recently, the ubiquity of neuronal cilia as well as possible clues about their functions, have been revealed by the use of two receptor antibodies that label mainly cilia, with minimal staining of somata or neuropil. In most regions of rat and mouse central nervous system, an antibody to somatostatin receptor subtype 3 (sst3) labels a single primary cilium per neuron (Händel et al., 1999; Schulz et al., 2000; Stepanyan et al., 2003). The antibody's identity was substantiated by demonstrating that it stains HEK-293 cells after transfection with sst3 mRNA, and by showing correspondence between the distribution of sst3 immunoreactivity and sst3 mRNA (Händel et al., 1999). Serotonin-6 receptor immunolabeling was localized to the plasma membrane of neuronal cilia in four brain regions (Brailov et al., 2000; Hamon et al., 1999), one of which also has neuronal cilia with sst3 receptors. As evidence for specificity, immunostained cilia were reduced in number afterintraventricular antisense serotonin-6 receptor mRNA(Hamon et al., 1999). We have found a particularly widespread distribution of immunoreactive neuronal cilia in the rat central nervous system (Fuchset al., 2003; Hughes et al., 2002), using an antibody of uncertain identity, raised against Gα11. None of the three antibodies have shown cilia in glial cells. The differences in distribution of the three antibodies among neuronal populations indicate a degree of biochemical heterogeneity, consistent with the regional and cellular diversity that exemplifies the brain. The regional heterogeneity among neuronal cilia may provide clues to their functions.

2 Not all neuronal cilia are alike: regional variations in function?

We observed that for nearly all regions of the rat CNS, each neuron appears to have a solitary cilium(Fig. 1) as visualized by distinctive staining with an antibody raised to an N-terminal peptide from subunit of mouse G11 (Santa Cruz Biotechnology, Santa Cruz, CA, USA) (Fuchs et al., 2000; Hughes et al., 2002), which is the α-subunit of G11, a G protein that couples many neurotransmitter receptors to their second messenger responses. Staining in cilia was completely abolished by preabsorption with the blocking peptide, but it is instructive that these tests failed to confirm the antibody's identity: (1) a second antibody, to C-terminal Gαq/11(Santa Cruz Biotechnology, Santa Cruz, CA, USA), did not stain rat cilia; and (2) although neither antibody stained cilia in mice, Gα11staining was not reduced elsewhere in Gα11knockout mice (e.g., in beaded axons). While the antigen remains unknown, the antibody has been useful for identifying cilia (Fig. 2). It colocalized at the light microscopic level with sst3 receptor antibody (Fig. 3), which in turn has been localized to neuronal cilia membranes (Händel et al., 1999). Each cilium emerged from a soma stained with anti-NeuN, a marker for neurons. In pyramidal-shaped cortical neurons, where polarity is evident, cilia generally originated from the apical region of the soma. Mean cilium length varied across brain regions (Fig. 4), ranging from 2.1 μm to 9.4 μm across 23 regions of the central nervous system. The ratio of cilium length to soma area ranged from 0.004 in the spinal cord ventral horn and 0.013 in the ventral posterior thalamus, to 0.080 in periventricular hypothalamus and 0.073 in the dorsal horn. In reviewing the list of cilia length for each brain region, we noticed that many regions with particularly long cilia were near brain ventricles. This impression was confirmed statistically: proximity to a ventricular surface correlated positively with cilium length (r=0.61, P<0.01; n=23 regions), and the relationship was strongest within 2 mm of a ventricular surface. This correlation was not a secondary effect of soma size distribution, as (a) it also held for the ratio of cilium length to soma area (r=0.48, P<0.05), and (b) cilium length was unrelated to soma size across brain regions (r=0.05, P>0.05). These results suggest that primary neuronal cilia may detect gradients of peptides and other substances that originate in the cerebrospinal fluid and are conveyed by the extracellular milieu. This finding is reminiscent of the ependymal cells, glial cells, and specialized neurons that extend cilia or microvilli into ventricles in lower vertebrates or during ontogeny, ostensibly to sample the chemistry of cerebrospinal fluid (Dale et al., 1987; Tramontin et al., 2003; Vigh and Vigh-Teichmann, 1998).

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Fig. 1

Solitary cilia labeled with an antibody raised to Gα11(green) are evident on neuron cell bodies counterstained with anti-NeuN (red), a neuronal marker. This section is from the rat dorsomedial hypothalamus. Scale bar, 20 μm

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Fig. 2

Tufts of cilia on ependymal cells lining the 4th ventricle as well as cilia on neurons in the central gray area, are stained with DAB-tagged antibody raised to Gα11(brown). Cell bodies are counterstained for Nissl substance. Scale bar, 10 μm

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Fig. 3

Neurons from the ventromedial hypothalamus are dual-labeled to illustrate colocalization of the antibody raised to Gα11(A) with somatostatin-3 receptor antibody (B). Scale bar, 10 μm

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Fig. 4

Regional heterogeneity in cilia length is illustrated by comparing the ventromedial hypothalamic nucleus (A) and the ventral posteromedial thalamic nucleus (B). As in Fig. 1, green is the antibody raised to Gα11, red is NeuN. Scale bar, 10 μm

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3 Primary cilia as sensors

3.1 Information from sensory cilia

Specialized sensory cilia convey a large portion of the stream of information to the vertebrate brain. These cilia are typically nonmotile and are thought to be derived from primary cilia (Dubruille et al., 2002; Menco and Farbman, 1985a). Olfactory cilia are endowed with a sensory transduction kit complete with olfactory receptors, G proteins, adenylyl cyclase, and ion channels that initiate depolarization of the ciliated olfactory neuron. Sensory neurons in acoustico-vestibular systems have slightly modified cilia, either transiently during development or persisting through adulthood (Sobkowicz et al., 1995). Visual systemphotoreceptors are highly modified cilia. The phototransducing outer segment no longer resembles the ancestral cilium. The connecting cilium, which bears the 9+0 pattern of microtubules, shuttles supplies between the inner and outer segments (Liu et al., 1999; Pazouret al., 2002).

Do neuronal primary cilia detect chemical, mechanical, or photic stimuli? It seems evident that cilia accomplish sensory transduction of some sort, as has been proposed over the decades for primary cilia of various cell types. In neuronal cilia, chemosensing is the best supported to date, thanks to the discovery that neuronal cilia have receptors for somatostatin and serotonin, which can serve as neuromodulatory or neurohormonal signals. Localization of the G-proteins and effectorsthat are linked to these receptors in cilia awaits the development of suitable antibodies.

3.2 Sensing similarities with other primary cilia

Neuronal primary cilia as a research topic is quite new, and it is imperative that we build upon what is known about other cilia, especially primary cilia (cf. Primary Cilium Resource website). Neuronal ciliaresemble other primary cilia ultrastructurally, but little is known about similarities in function or molecular composition. In kidney, primary cilia extend into the tubular lumen and bend with the flow of fluid, resulting in elevated intracellular Ca²⁺levels (Praetorius and Spring, 2001, 2003). Polycystin-2 in the ciliary membrane contributes to Ca²⁺entry (Nauli et al., 2003). A similar story is unfolding for mouse embryonic peripheral node cells (McGrath et al., 2003), whose nonmotile primary cilia bend with directional fluid movement generated by motile cilia in the neighboring central node region. Again, polycystin-2 in the ciliary membrane apparently is involved in mediating mechanotransduction. The resultant asymmetry in Ca²⁺elevationswithin the peripheral node region promotes left–right differences in gene expression in the developing organism. Mechanosensing roles have been proposed for primary cilia on osteocytes (Whitfield, 2003) and chondrocytes (Poole et al., 1997, 2001). Mechanosensing roles may be most suited to cilia that are surrounded by fluid. In the central nervous system, mechanical stress-induced effects have been studied in connection with injury and pathology. The cerebrospinal fluid and meninges normally cushion the brain against injury, but it is conceivable that neuronal cilia sense mechanical stimuli from daily activity.

Other possible sensory functions that neuronal cilia and other primary cilia might have include monitoring osmolarity or pH. The cilium's small volume relative to surface area could allow cilia to change volume quickly in response to small changes in osmolarity; also, there is precedence for osmoreception in sensory cilia of C. elegans (Tobin et al., 2002). Extracellular pH can be affected by momentary reduction of O2relative to CO2which accompanies neural activity and is followed by a rapid increase in blood supply to the activated area. Whether neuronal cilia participate in the monitoring of either osmolarity or pH is unknown.

4 Primary cilia as responders

Sensing in cilia is useful insofar as the end result is an adaptive response. The cilia of sensory cells transduce stimulus energy into changes in ion permeability, which in turn translates as changes in membrane potential. But how can a tiny cilium get the attention of a large neuron? Based on the information that olfactory cilia—an average of 11 per neuron in rat (Menco and Farbman, 1985b)—can trigger action potentials in an olfactory receptor neuron, it seems likely that a single primary cilium could confer upon a neuron enough bias in membrane potential to affect neuronal firing rate. The small diameter of the cilium predicts high input resistance and a large membrane potential for a given current. Electrical signals generated in the relatively short cilia might diminish less than some dendritic postsynaptic signals en route to the soma. The cilium's narrow geometry also seems ideal for retaining second messengers such as Ca²⁺. In neuronal soma and axon terminals, Ca²⁺transients are typically ephemeral, subject to immediate diffusion and a battery of strategies for defending baseline Ca²⁺levels. Levels of Ca²⁺and other second messengers in the cilium might be uniquely sustainable, resulting in prolonged changes in ionic conductances and other cellular effects.

Neurons are already exquisitely chemoreceptive. Their elaborate dendritic trees locally sense specific chemicals such as neurotransmitters, neurotrophins, hormones, and ions—so wouldn't neuronal cilia be extraneous? While synaptic membrane is dedicated to communication with other neurons, the ciliary membrane could survey the external milieu. Additionally, and perhaps most unique to the nervous system, select neuronal groups might be recruited in concert through endocrine and paracrine receptors common to their cilia, leading to specific physiological and behavioral responses.

Cilia might help protect neurons from sustained high-frequency firing, which can jeopardize a neuron's energy reserves or produce excitotoxic cell death. Over-excitation is believed to contribute to neuronal cell death in neurodegenerative diseases and other stressful conditions. If cilia can sense effects of vigorous neural activity such as altered levels of glutamate, K⁺, CO2, pH, or glucose, subsequent changes in ionic permeabilities of the cilia membrane might come to the rescue by hyperpolarizing the neuron's resting potential, which could reduce the frequency of action potentials and thereby restrain metabolic demands.

5 Cilia in development

The relationship between cilia and cell proliferation is a topic of long-standing interest (Fonte et al., 1971; Ho and Tucker, 1989). Cilia emerge from basal bodies, which originate as centrosomes, which in turn organize the mitotic spindle. Precursor cells resorb cilia just before mitosis and regrow them afterwards. It is tempting to consider that cilia may mediate influences from the extracellular milieu on cell proliferation and differentiation. Ca²⁺levels are implicated in mediating many signals that influence whether a cell shall divide, die, or differentiate. The cilium is strategically situated to pass along such signals from its location adjacent to the basal body/centriole, close to the Golgi apparatus and not far from the nucleus.

In early fetal development, neurogenic precursors—radial glia and many astrocytes in the subventricular zone—have a primary cilium which projects into the ventricular lumen (Tramontin et al., 2003). Few details are known about the development of neuronal cilia in fetal stages (Cohen et al., 1988; Cohen and Meininger, 1987). Interestingly, they emerge transiently from olfactory neurons in prenatal development before being replaced by specialized olfactory cilia (Menco and Farbman, 1985a). Neuronal cilia were also described in some regions of early postnatal rat brain (Del Cerro and Snider, 1967, 1969; Lafarga et al., 1980). We have observed rapid appearance of Gα11-immunostained neurons in rat spinal cord and various brain regions over the first few days after birth, but we do not yet know whether this reflects the genesis of cilia or of stainability. It is noteworthy that somatostatin, serotonin, and many other neurotransmitters and hormones affect neural proliferation in fetal stages well before synaptic signaling (Ferjoux et al., 2000; Nguyen et al., 2001). While stem cells add neurons to some brain regions even in maturity (Banasr et al., 2001), neurons themselves are postmitotic and do not divide. If indeed cilia do influence a proliferation of neuronal precursors, the receptors and associated response mechanisms might be retained for postmitotic needs, such as cell differentiation and maturation.

6 Neuronal cilia depend on intraflagellar transport; clinical implications

We recently found that most neuronal cilia appeared to be absent in mutant Tg737^orpkmice, suggesting that the intraflagellar transport protein polaris (IFT88), which is necessary for ciliogenesis in various cell types (Pazour et al., 2000; Yoder et al., 2002), is also important for neuronal cilia. Again, heterogeneity is evidenced by the observation that while many brain regions in IFT88-deficient mice lacked sst3-immunoreactive cilia, some brain regions retained shortened cilia, including much of the olfactory bulb, layer 2 of the piriform cortex, and all layers of neocortex. There is evidence that intraflagellar transport proteins are involved in active maintenance of cilia, through a dynamic balance between synthesis and breakdown of the ciliary axoneme (Baker et al., 2003; Marshall and Rosenbaum, 2001). The importance of intraflagellar transport proteins (Rosenbaum and Witman, 2002; Sloboda, 2002) in neurons of these mice supports the proposal that neuronal cilia are actively maintained and have fundamental properties in common with other primary cilia. The mutant brains were clearly hydrocephalic, as previously reported by Taulman et al. (2001). A lack of ependymal cilia to move the cerebrospinal fluid has often been assumed to cause hydrocephalus, although this causal relationship is in dispute (Roth et al., 1985, 1988). The next challenge is to unravel the sequelae of ciliary defects. Recent awareness that neurons have cilia calls for a reevaluation of clinical cases involving brain cysts and other neurological abnormalities that accompany symptoms of defective motile or nonmotile cilia in other tissues. We would expect to see individual differences in the constellations of neurological symptoms depending on which cilia-related genes are affected, especially in view of the heterogeneity of gene expression among neuronal cilia.

Acknowledgements

We thank our students who participated in the research, particularly Rhome Hughes for his morphometric study of neuronal cilia. Those currently working on the Tg737^orpkmouse brains include Ankur Patel, Rajin Shahriar, Suman Pasapuleti, and Weilan Zuo. We are grateful to Dr Gregory Pazour for providing the Tg737^orpkbrains. This research was supported by NIMH MH41865 (JLF), NIH NS41891 (HDS), and grants from the University of North Texas.

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Received 30 September 2003; accepted 4 November 2003

doi:10.1016/j.cellbi.2003.11.008

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