Ciliopathies: Primary Cilia and Signaling Pathways in Mammalian Development

1.1 Ciliopathies, an emerging class of human genetic diseases The physiological role of motile cilia or flagella in cell locomotion, sexual reproduction and fluid movements is well known. In 1898, the Swiss anatomist KW Zimmerman first described cilia on the surface of mammalian cells, for which he suggested a sensory role. His findings were largely ignored until the late 1960s, when Wheatley, using the electron microscope, stumbled upon a properly sized bubble in his histological preparation, verifying it as the cilium described by Zimmerman 63 years earlier[1]. Although it became known that all cells, from green alga Chlamydomonas to human cells – especially kidney cells– possessed a nonmotile cilium, it was initially considered a vestigial structure with no clear function. Recent discoveries have assigned novel functions to primary (nonmotile) cilia, ranging from mechanosensory in maintaining cellular homeostasis, to participation in signal transduction pathways that regulate intracellular Ca2+levels. Furthermore, the cilium is now emerging as an essential organelle in morphogenesis, important to key developmental pathways such as Sonic Hedgehog (Shh) and Wnt (planar cell polarity (PCP) pathways). 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. Defects in cilia formation or function have profound effects on anatomical development and the physiology of multiple organ systems such as death of photoreceptors, kidney tubule cysts, extra limb digits and brain malformation [2, 3]. Alterations in ciliary function also play a role in specific organ diseases (polycystic kidney disease, pigmentosa retinitis...) and pleiotropic phenotypes (Bardet-Bield Syndrome, Alstrom S., Meckel-Gruber S., Oro-Facio-Digital S...), until recently of unknown origin. Our greater knowledge of genetics and the recognized role of cilium in morphogenetic signaling pathways, especially in neurogenesis, bring Bronowski’s phrase “All science is the search for unity in hidden likenesses” to life [4].