Cilia and the brain

Participants :

Eva S. Anton, Claudia Bagni, Alexandre Benmerah, Oliver Blacque (organisateur), Juan Burrone, Tom Dufor, Peter K. Jackson, Alex L. Kolodkin, Kirk Mykytyn, Maxence Nachury, Carolyn Ott, Timothy A. (Tim) Ryan, Patricia Salinas, Piali Sengupta (organisateur), Nathalie Spassky, Lauren Tereshko, Gina Turrigiano (organisateur), Enza Maria Valente

Cilia et le cerveau / Cilia and the Brain
by Piali Sengupta, Oliver E. Blacque and Gina Turrigiano
11 – 16 March, 2019

Summary

Cilia are microtubule-based signalling structures found on nearly all central nervous system (CNS) cell types. However, despite their emerging importance within the CNS especially in relation to cilia-related brain pathologies, how cilia modulate neuronal properties remains largely unknown. Eighteen researchers from the United States and Europe including two junior researchers met to discuss how cilia may contribute to the development and function of central neurons. The seminar aimed to introduce neuroscientists to cilia biology, and conversely, to educate cilia biologists in the complexity of the nervous system, with the goal of initiating new research for studying cilia in the brain. The seminar included researchers working on cilia-related neurodevelopmental disorders, the molecular mechanisms of ciliary signalling in neurons and other cell types, visualization of cilia in the brain, neuronal connectivity pathways, and mechanisms of synaptic signalling and neuronal plasticity. Many different experimental approaches were represented, embracing techniques in cell biology, developmental neuroscience, clinical genetics, cellular and systems neuroscience, and cellular imaging. Attendees presented work from multiple cell and animal model systems including C. elegans, mouse, and human cultured cells. The presentations lead to extensive discussions around important themes such as: (i) the roles for cilia at different stages of neuronal development, (ii) ciliary signaling in neurons, (iii) shared compartmentalization mechanisms between cilia and dendritic spines, (iv) genotype-phenotype correlations in ciliary diseases with CNS disruption, (v) transmission of ciliary signals to distant neuronal sites, and (vi) the types of cilia on neurons. Participants reported that the meeting was informative and exciting, highlighted new avenues of research, and allowed for the establishment of new collaborations.

Keywords: cilia, ciliopathies, signaling, neurons, central nervous system

Review

Overall goal of the seminar

Primary cilia are sensory organelles found on nearly all mammalian cell types, including mature neurons of the central nervous system (CNS). Defects in these organelles disrupt the development and maintenance of many tissue types, including the brain. However, despite intriguing hints that primary cilia play critical roles in the maintenance and plasticity of neurons and neuronal circuits, the roles of cilia in central neurons are largely unknown and understudied. The goal of this seminar was to bring together cilia biologists and neuroscientists to explore the role of cilia in the CNS, with an emphasis on how ciliary signaling impacts both the developing and mature brain.

General overview of presentations

Participants were divided roughly equally between cilia biologists and neuroscientists. A subset of participating cilia biologists also have expertise in neuroscience. 15 of the 18 participants were Principal Investigators, with the remainder comprising a PhD student, a postdoctoral fellow, and a Senior Scientist. The talks were lively and interactive, and extensive time was allocated during and after the presentations for questions, clarifications, and the discussion of emerging ideas. In particular, since several neuroscientists were unfamiliar with cilia and vice versa, each presentation included detailed background information along with descriptions of recent work in the research area of the presenter. The seminar concluded with a discussion of several key themes that were raised repeatedly throughout the presentations, which lead to suggestions and ideas for future work in this exciting area.

Major themes

Do cilia play different roles at different stages of neuronal development? Cilia contribution to neuronal functions has typically been assessed using gene knockouts that disrupt cilia throughout all stages of development. However, neuronal development proceeds through multiple stages (eg. neurogenesis, cell fate specification, process outgrowth, synapse formation, circuit refinement), and moreover, neuronal circuits continue to be modified in the adult. Although roles for cilia in the embryonic brain are established, their functions in the adult brain remain mysterious. There is a great need to conditionally disrupt cilia at different time-points to uncover how ciliary signaling contributes to distinct stages of embryonic brain development, and the maintenance and plasticity of the adult brain.

Why is signaling via cilia important in neurons? Neurons are characterized by complex dendritic and axonal morphologies, which mediate neuronal communication via chemical and electrical synapses, as well as via extrasynaptic neuropeptidergic signaling. A major discussed issue was why these cells would also require signaling via a small (typically <10 mm) ciliary structure, and whether such signaling could result in different cellular effects than signaling from elsewhere in the cell. Participants agreed that concentrating signaling molecules within cilia may allow for more effective, localized signaling. Moreover, the compartmentalization of multiple signaling pathways within cilia may permit efficient cross-talk and modulation. A conclusion was that this was a major issue that requires investigation in the nervous system.

What is the protein content of neuronal cilia? The brain is characterized by the presence of many thousands of different cell types. A subset of signaling proteins such as the somatostatin receptor 3 and neuropeptide Y receptors have been shown to be specifically (see below) localized to neuronal cilia in defined brain regions such as in the hippocampus and hypothalamus. However, whether these receptors are present on all or only a subset of neurons in these brain regions is unknown. Moreover, additional components of cilia in these and other brain regions are largely unidentified. There is a great need to systematically catalog the ciliary proteome as a function of neuronal cell type and developmental stage across the brain in order to understand how ciliary signaling may modulate neuronal functions.

Are ciliary proteins cilia-specific? A major point of discussion was whether proteins described as cilia-specific are truly only localized to cilia. This is critical to establish since if proteins are also extra-ciliary, it would be difficult to dissect their contributions from cilia as compared to elsewhere in the plasma membrane. It was also noted that this may be technically challenging to assess due to the larger cell membrane volume compared to the ciliary membrane.

Do cilia and synapses / dendritic spines share similar compartmentalization mechanisms? There was significant discussion as to whether ciliary compartmentalization paradigms operate at synapses/dendritic spines. Are there diffusion barriers or lipid gates at the dendritic spine neck analogous to those found at the ciliary base, and if so, could they employ some of the ciliary gating machinery? Currently such barriers are not known in spines. Also, do components of ciliary transport machinery (eg., IFT-A/B and BBSome complexes) have transport-associated roles in maintaining synapse/spine composition and structure? Indeed, there are reports of IFT and BBS proteins localizing at synaptic structures.

Genotype-phenotype correlations in ciliopathies with CNS disruption? We do not have a good understanding as to why ciliopathies such as Joubert Syndrome (JBTS) can present with large symptomatic variation across different patient cohorts. Mutations in the same gene can give rise to a strikingly different phenotype. Discussion centered around the importance of investigating allele-specific effects on the JBTS phenotype, and how cell-specific mechanisms of JBTS gene function can influence the disease phenotype.

Where are cilia localized on neurons? The location of cilia in different cell types in different parts of the brain are unknown. Initial electron microscopy reconstructions of the brain appear to demonstrate tremendous heterogeneity in the sites and structures of neuronal cilia. Establishing this issue is important since ciliary signaling from different cellular locations may influence neuronal properties via different pathways.

How are signals from cilia transmitted to distant neuronal sites? A hallmark of many neurons is the presence of long processes with synapses present at sites as distant as several meters from the cell body. How are signals from the cilia transmitted to these distant sites? Possibilities are via second messenger molecules generated by ciliary signaling, or longer-term effects mediated by transcriptional mechanisms initiated by signals from the cilia.

What role might ciliary signaling play in the maintenance of neuronal activity? Maintaining the proper balance between excitatory and inhibitory synaptic input is crucial for neuronal circuit function. An intriguing possibility is that cilia integrate disparate signals from many sources in a neuronal circuit, and then use those signals to adjust excitatory or inhibitory synaptic strength. This model is highly speculative but intriguing preliminary results suggest it should be investigated further.

Summary of outcomes from seminar

The seminar successfully interested participating neuroscientists in the roles of cilia in the brain, and informed cilia biologists about brain complexity and function. The seminar also allowed two groups of scientists who may not otherwise communicate to meet and interact extensively. The presentations and discussions highlighted the many fascinating and complex questions in the field, and led to the establishment of at least two collaborations to begin to address some of these issues. We thank the Fondation for their support of this very successful and interesting seminar and look forward to learning more about the functions of cilia in the brain in the future.

Eva Anton Claudia Bagni Alexandre Benmerah Oliver Blacque Juan Burrone Tom Dufor Peter Jackson Alex Kolodkin Kirk Mykytyn Maxence Nachury Carolyn Ott Tim Ryan Patricia Salinas Piali Sengupta Nathalie Spassky Lauren Tereshko Gina Turrigiano Enza Maria Valente Cilia et le cerveau - Cilia and the brain
This entry was posted in Activities, Reviews and tagged , . Bookmark the permalink.