Neuronal ciliary signaling in homeostasis and disease (original) (raw)

Primary Cilia in Brain Development and Diseases

The American journal of pathology, 2017

The primary cilium, a sensory appendage that is present in most mammalian cells, plays critical roles in signaling pathways and cell cycle progression. Mutations that affect the structure or function of primary cilia result in ciliopathies, a group of developmental and degenerative diseases that affect almost all organs and tissues. Our understanding of the constituents, development, and function of primary cilia has advanced considerably in recent years, revealing pathogenic mechanisms that potentially underlie ciliopathies. In the brain, the primary cilia are crucial for early patterning, neurogenesis, neuronal maturation and survival, and tumorigenesis, mostly through regulating cell cycle progression, Hedgehog signaling, and WNT signaling. We review these advances in our knowledge of primary cilia, focusing on brain development, and discuss the mechanisms that may underlie brain abnormalities in ciliopathies.

The roles of cilia in developmental disorders and disease

Development, 2006

Cilia are highly conserved organelles that have diverse motility and sensory functions. Recent discoveries have revealed that cilia also have crucial roles in cell signaling pathways and in maintaining cellular homeostasis. As such, defects in cilia formation or function have profound effects on the development of body pattern and the physiology of multiple organ systems. By categorizing syndromes that are due to cilia dysfunction in humans and from studies in vertebrate model organisms, molecular pathways that intersect with cilia formation and function have come to light. Here, we summarize an emerging view that in order to understand some complex developmental pathways and disease etiologies, one must consider the molecular functions performed by cilia.

Primary cilia in neurodevelopmental disorders

Nature reviews. Neurology, 2014

Primary cilia are generally solitary organelles that emanate from the surface of almost all vertebrate cell types. Until recently, details regarding the function of these structures were lacking; however, extensive evidence now suggests that primary cilia have critical roles in sensing the extracellular environment, and in coordinating developmental and homeostatic signalling pathways. Furthermore, disruption of these functions seems to underlie a diverse spectrum of disorders, known as primary ciliopathies. These disorders are characterized by wide-ranging clinical and genetic heterogeneity, but with substantial overlap among distinct conditions. Indeed, ciliopathies are associated with a large variety of manifestations that often include distinctive neurological findings. Herein, we review neurological features associated with primary ciliopathies, highlight genotype-phenotype correlations, and discuss potential mechanisms underlying these findings.

Various facets of vertebrate cilia: motility, signaling, and role in adult neurogenesis

Proceedings of The Japan Academy Series B-physical and Biological Sciences, 2009

Cilia are microtubule-based cellular organelles that are widely distributed in vertebrate tissues. They were rst observed hundreds of years ago. Recent studies indicate that this small organelle plays important roles in numerous physiological phenomena, including tissue morphogenesis, signal transduction, determination of left-right asymmetry during development, and adult neurogenesis. Ciliopathies, syndromes resulting from a genetic disorder of cilial components, frequently have complex eects involving many organ systems, owing to the broad distribution of cilia in the body.

Role of primary cilia in brain development and cancer

Current Opinion in Neurobiology, 2010

The primary cilium, a hair-like extension from a cell's surface, acts as a sensory organelle to receive signals that regulate cellular behavior and physiology. Like most mammalian cells, neural progenitors and neurons have primary cilia. Recent studies show that this tiny projection plays important roles in brain development and diseases. Ciliary mutant mice show defects in brain patterning, progenitor proliferation, and specification of adult neural stem cells. Primary cilia also have dual opposing functions in the development of brain tumors. Ciliary defects are associated with genetic syndromes that frequently have neurological symptoms. Understanding the multifaceted roles that primary cilia have in brain development will provide important insights into the mechanism of brain development and diseases.

Modeling ciliopathies: Primary cilia in development and disease

Current topics in developmental biology, 2008

Primary (nonmotile) cilia are currently enjoying a renaissance in light of novel ascribed functions ranging from mechanosensory to signal transduction. Their importance for key developmental pathways such as Sonic Hedgehog (Shh) and Wnt is beginning to emerge. The function of nodal cilia, for example, is vital for breaking early embryonic symmetry, Shh signaling is important for tissue morphogenesis and successful Wnt signaling for organ growth and differentiation. When ciliary function is perturbed, photoreceptors may die, kidney tubules develop cysts, limb digits multiply and brains form improperly. The etiology of several uncommon disorders has recently been associated with cilia dysfunction. The causative genes are often similar and their cognate proteins certainly share cellular locations and/or pathways. Animal models of ciliary gene ablation such as Ift88, Kif3a, and Bbs have been invaluable for understanding the broad function of the cilium. Herein, we describe the wealth of...

The Multifaceted Roles of Primary Cilia in the Development of the Cerebral Cortex

Frontiers in Cell and Developmental Biology, 2021

The primary cilium, a microtubule based organelle protruding from the cell surface and acting as an antenna in multiple signaling pathways, takes center stage in the formation of the cerebral cortex, the part of the brain that performs highly complex neural tasks and confers humans with their unique cognitive capabilities. These activities require dozens of different types of neurons that are interconnected in complex ways. Due to this complexity, corticogenesis has been regarded as one of the most complex developmental processes and cortical malformations underlie a number of neurodevelopmental disorders such as intellectual disability, autism spectrum disorders, and epilepsy. Cortical development involves several steps controlled by cell–cell signaling. In fact, recent findings have implicated cilia in diverse processes such as neurogenesis, neuronal migration, axon pathfinding, and circuit formation in the developing cortex. Here, we will review recent advances on the multiple ro...