Primary Cilia Signaling Shapes the Development of Interneuronal Connectivity

Guo, Jiqing; Otis, James M.; Higginbotham, Holden; Monckton, Chase; Cheng, Jr Gang; Asokan, Aravind; Mykytyn, Kirk; Caspary, Tamara; Stuber, Garret D.; Anton, E. S.

doi:10.1016/j.devcel.2017.07.010

Cited by 104 publications

(106 citation statements)

References 89 publications

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“…Within the adult CNS, dysfunction of ciliary trafficking is linked to retinal degeneration (Wheway et al, 2014), and conditional loss of the ciliary protein ARL13B from mouse striatal interneurons both during their development as well as in the mature brain, results in changes in their morphology and connectivity (Guo et al, 2017). Our work extends these findings and provides additional strong evidence that primary cilia and signals mediated by these organelles are important to maintain the morphology of neurons as well as their connections.…”

Section: Discussionsupporting

confidence: 69%

“…Nevertheless, newly emerging evidence suggests that cilia and ciliary signaling may be important in this context: Cilia are required for the establishment of synaptic connectivity in hippocampal dentate granule neurons (Kumamoto et al, 2012) and in striatal interneurons (Guo et al, 2017). Neuronal cilia also concentrate a wide array of GPCRs and other neuropeptide and neurotrophin receptors important for complex neurological functions (Berbari et al, 2008;Domire et al, 2011;Green et al, 2012;Guadiana et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

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TTBK2 and primary cilia are essential for the connectivity and survival of cerebellar Purkinje neurons

Bowie

Goetz

2019

Preprint

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Primary cilia are vital signaling organelles that extend from most types of cells, including neurons and glia. However, their function, particularly on neurons in the adult brain, remains largely unknown. Tau tubulin kinase 2 (TTBK2) is a critical regulator of ciliogenesis, and is also mutated a hereditary neurodegenerative disorder, spinocerebellar ataxia type 11 (SCA11).Here, we show that conditional knockout of Ttbk2 in adult mice results in degenerative cerebellar phenotypes that recapitulate aspects of human SCA11 including motor coordination deficits, loss of synaptic connections to Purkinje cells (PCs), and eventual loss of PCs. We also find that the Ttbk2 conditional mutant mice quickly lose cilia throughout the brain. We show that conditional knockout of the key ciliary trafficking gene Ift88 in adult mice results in nearly identical cerebellar phenotypes to those of the Ttbk2 knockout, supporting disruption of ciliary signaling as a key driver of these phenotypes. Our data suggest that primary cilia play an integral role in maintaining adult neuronal function, and offers novel insights into the mechanisms involved in neurodegeneration.

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Section: Discussionsupporting

confidence: 69%

Section: Introductionmentioning

confidence: 99%

TTBK2 and primary cilia are essential for the connectivity and survival of cerebellar Purkinje neurons

Bowie

Goetz

2019

Preprint

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“…SSTR3 and SSTR5 were similarly strongly co-localised with all types of interneurons and this co-localisation ranged from 74 to 97%. Some authors have shown that in mouse and rat, SSTR3 is selectively targeted to primary neuronal cilia, a specialised microtubule-based organelle that play a role in neuronal signaling and the regulation of synaptic connectivity (Handel et al 1999;Whitfield 2004;Guo et al 2017). We detected SSTR3 in membrane and cytoplasm of neuronal cell bodies and dendrites, while observing the cilia-like shapes as well.…”

Section: Discussionmentioning

confidence: 60%

Somatostatin receptors (SSTR1-5) on inhibitory interneurons in the barrel cortex

et al. 2019

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Inhibitory interneurons in the cerebral cortex contain specific proteins or peptides characteristic for a certain interneuron subtype. In mice, three biochemical markers constitute non-overlapping interneuron populations, which account for 80-90% of all inhibitory cells. These interneurons express parvalbumin (PV), somatostatin (SST), or vasoactive intestinal peptide (VIP). SST is not only a marker of a specific interneuron subtype, but also an important neuropeptide that participates in numerous biochemical and signalling pathways in the brain via somatostatin receptors (SSTR1-5). In the nervous system, SST acts as a neuromodulator and neurotransmitter affecting, among others, memory, learning, and mood. In the sensory cortex, the co-localisation of GABA and SST is found in approximately 30% of interneurons. Considering the importance of interactions between inhibitory interneurons in cortical plasticity and the possible GABA and SST co-release, it seems important to investigate the localisation of different SSTRs on cortical interneurons. Here, we examined the distribution of SSTR1-5 on barrel cortex interneurons containing PV, SST, or VIP. Immunofluorescent staining using specific antibodies was performed on brain sections from transgenic mice that expressed red fluorescence in one specific interneuron subtype (PV-Ai14, SST-Ai14, and VIP-Ai14 mice). SSTRs expression on PV, SST, and VIP interneurons varied among the cortical layers and we found two patterns of SSTRs distribution in L4 of barrel cortex. We also demonstrated that, in contrast to other interneurons, PV cells did not express SSTR2, but expressed other SSTRs. SST interneurons, which were not found to make chemical synapses among themselves, expressed all five SSTR subtypes.

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“…These phenotypes are in line with the neurodevelopmental and GABAergic hypotheses of schizophrenia. In addition, primary cilium signaling is required for postmigration developmental processes in interneurons, such as connectivity and circuit activity (Guo et al, ). In fact, selective loss of a ciliary‐specific GTPase in interneurons alters GABAergic neuronal morphology and synaptic connectivity, therefore, altering excitatory/inhibitory activity balance (Guo et al, ).…”

Section: Neurodevelopmental Disorders Associated To Bloc‐1 and Borc Cmentioning

confidence: 99%

“…In addition, primary cilium signaling is required for postmigration developmental processes in interneurons, such as connectivity and circuit activity (Guo et al, ). In fact, selective loss of a ciliary‐specific GTPase in interneurons alters GABAergic neuronal morphology and synaptic connectivity, therefore, altering excitatory/inhibitory activity balance (Guo et al, ). This unbalance in excitatory/inhibitory activity is a central mechanism of neurodevelopmental disorders and it is a phenotype shared by Bloc1s8 sdy/sdy and other mouse models of neurodevelopmental disorders (Gogolla et al, ; Carlson et al, ; Yizhar et al, ).…”

Section: Neurodevelopmental Disorders Associated To Bloc‐1 and Borc Cmentioning

confidence: 99%

Neurodevelopmental disease mechanisms, primary cilia, and endosomes converge on the BLOC‐1 and BORC complexes

Hartwig

Monis

Chen

et al. 2017

Developmental Neurobiology

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The biogenesis of lysosome-related organelles complex-1 (BLOC-1) and the bloc-one-related complex (BORC) are the cytosolic protein complexes required for specialized membrane protein traffic along the endocytic route and the spatial distribution of endosome-derived compartments, respectively. BLOC-1 and BORC complex subunits and components of their interactomes have been associated with the risk and/or pathomechanisms of neurodevelopmental disorders. Thus, cellular processes requiring BLOC-1 and BORC interactomes have the potential to offer novel insight into mechanisms underlying behavioral defects. We focus on interactions between BLOC-1 or BORC subunits with the actin and microtubule cytoskeleton, membrane tethers, and SNAREs. These interactions highlight requirements for BLOC-1 and BORC in membrane movement by motors, control of actin polymerization, and targeting of membrane proteins to specialized cellular domains such as the nerve terminal and the primary cilium. We propose that the endosome-primary cilia pathway is an underappreciated hub in the genesis and mechanisms of neurodevelopmental disorders. © 2017 Wiley Periodicals, Inc. Develop Neurobiol 78: 311-330, 2018.

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Primary Cilia Signaling Shapes the Development of Interneuronal Connectivity

Cited by 104 publications

References 89 publications

TTBK2 and primary cilia are essential for the connectivity and survival of cerebellar Purkinje neurons

TTBK2 and primary cilia are essential for the connectivity and survival of cerebellar Purkinje neurons

Somatostatin receptors (SSTR1-5) on inhibitory interneurons in the barrel cortex

Neurodevelopmental disease mechanisms, primary cilia, and endosomes converge on the BLOC‐1 and BORC complexes

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