Ciliary dysfunction in developmental abnormalities and diseases

Abstract

Cilia are small microtubule-based cellular appendages that are broadly classified as being either motile or immotile (primary cilia). Since their initial discovery several centuries ago, motile cilia have been of general interest to basic scientists and others who study the dynamics and physiological relevance of their motility. More recent discoveries have found that motile and immotile cilia, the later of which are present on nearly all cells in the mammalian body, also have major roles during development and in postnatal life. Dysfunction of the cilium is the basis for multiple human genetic disorders that have collectively been called the ciliopathies. The phenotypes associated with cilia dysfunction in mammals are diverse and include randomization of the left-right body axis, abnormalities in neural tube closure and patterning, skeletal defects such as polydactyly, cystic kidney, liver, and pancreatic diseases, blindness and anosmia, behavioral and cognitive defects, and obesity. The connection between disease and developmental defects due to the loss of ciliary function has brought the efforts of the biomedical research establishment to bear on this underappreciated and long overlooked organelle. Several groups have applied en silico, genetic, and biochemical approaches to identify the components of the cilia proteome. The resulting datasets have contributed to a remarkable increase in the rate at which human ciliopathy disease loci are being identified. This intense basic and clinical research interest has revealed that the cilium is a very complex sensory machine involved in transducing extracellular stimuli involved in many different signaling pathways into cellular responses. Although major advances have been made in understanding the importance of the cilium, it remains enigmatic how the cilium functions to coordinate signaling pathways and how loss of this organelle results in the severe defects observed in human ciliopathies.