Neurodevelopmental disorders (NDDs) impose a global burden, affecting an increasing number of individuals. While some causative genes have been identified, understanding the human-specific mechanisms involved in these disorders remains limited. Traditional gene-driven approaches for modeling brain diseases have failed to capture the diverse and convergent mechanisms at play. Centrosomes and cilia act as intermediaries between environmental and intrinsic signals, regulating cellular behavior. Mutations or dosage variations disrupting their function have been linked to brain formation deficits, highlighting their importance, yet their precise contributions remain largely unknown. Hence, we aim to investigate whether the centrosome/cilia axis is crucial for brain development and serves as a hub for human-specific mechanisms disrupted in NDDs. Towards this direction, we first demonstrated species-specific and cell-type-specific differences in the cilia-genes expression during mouse and human corticogenesis. Then, to dissect their role, we provoked their ectopic overexpression or silencing in the developing mouse cortex or in human brain organoids. Our findings suggest that cilia genes manipulation alters both the numbers and the position of NPCs and neurons in the developing cortex. Interestingly, primary cilium morphology is disrupted, as we find changes in their length, orientation and number that lead to disruption of the apical belt and altered delamination profiles during development. Our results give insight into the role of primary cilia in human cortical development and address fundamental questions regarding the diversity and convergence of gene function in development and disease manifestation. It has the potential to uncover novel pharmacological targets, facilitate personalized medicine, and improve the lives of individuals affected by NDDs through targeted cilia-based therapies.

SeminarNeuroscience

Neural circuit and genetic bases of behaviour in Platynereis larva

Gaspar Jekely

University of Exeter

Dec 9, 2020

We study the larval stages of the marine annelid Platynereis dumerilii, a powerful experimental system for neural circuits. With serial electron microscopy, we have reconstructed the entire nervous and effector systems of a Platynereis larva. We use neurogenetics, activity imaging, and behavioural experiments to understand circuit activity and how the nervous system controls behaviour and physiology. Platynereis is one of very few systems where these different approaches can be combined to study an entire nervous system. I will talk about circuits for the whole-body coordination of locomotor cilia and a hydrodynamic startle response for predator avoidance.

SeminarNeuroscience

Integrative modeling of Paramecium, a swimming neuron

Romain Brette

Institut de la Vision, Université Pierre-and-Marie-Curie

Sep 23, 2020

Paramecium is a unicellular organism that swims in fresh water using cilia. When it is stimulated (mechanically, chemically, optically, thermally, etc), it often swims backward then turns and swims forward again: this is called the avoiding reaction. This reaction is triggered by a calcium-based action potential. For this reason, it enjoyed a period of glory in the 1970s as a model organism for neuroscience. I will describe the behavior and electrophysiology of this “swimming neuron”, then I will present our ongoing attempts at developing an integrative quantitative model of Paramecium.

cilia

Latest

The cell biology of Parkinson’s disease: a role for primary cilia and synaptic vesicle pleomorphism in dopaminergic neurons

Beyond the synapse: SYNGAP1 in primary and motile cilia

Modeling human brain development and disease: the role of primary cilia

Neural circuit and genetic bases of behaviour in Platynereis larva

Integrative modeling of Paramecium, a swimming neuron

The atypical cilia of choroid plexus through developmental lenses

Braincils: Exploring the missing link between neuronal primary cilia dysfunction and neurodevelopmental disorders - hints from dental stem cell-derived brain organoids

A cell-autonomous role for primary cilia in long-range commissural axon guidance

The connection between primary cilia and the hypoxia-inducible factor-2alpha promotes the MEK/ERK signaling pathway

Growth/differentiation factor 15 influences primary cilia in neural stem cells in the ventricular-subventricular zone but not in the subgranular zone

Knockdown of Primary Ciliary Component Gene in Hypothalamic Paraventricular Nucleus Oxytocin Neurons Impairs Social Behavior

The peculiar cilia of olfactory sensory neurons

Role of the neuronal primary cilia-autophagy axis in the regulation of cognition during aging

Choroid plexuses carry nodal-like cilia that undergo axoneme regression from early adult stage

Cilia-mediated cerebrospinal fluid flow modulates neuronal and astroglial activity in the zebrafish larval brain

Hypoxia induces MEK/ERK signaling via primary cilia and the hypoxia-inducible factor-2alpha - a helping factor for neuronal cells to survive ischemia?

The hypoxia-inducible factor 1alpha and primary cilia – a functional analysis of the interplay in neuronal cells

Restorative potential of ciliary body cells in a retinal ganglion cell degeneration model

Influence of the ciliary proteasome on hypoxia-inducible factors

Investigating the role of centrosome-cilia axis in human cortical development orchestration and malformations

A novel microtubule doublet regulator in neuronal primary cilia

The role of tanycytic cilia on hypothalamic functions

The sweet taste receptor signaling at primary cilia involves an adenylate cyclase inhibitory mechanism