Читать книгу Pathology of Genetically Engineered and Other Mutant Mice - Группа авторов - Страница 101

The immotile/primary cilia are present on almost all types of cells, and their primary function is to transduce signals from the environment or surrounding cells. For many decades after their discovery, it was thought that the immotile primary cilia were purely vestigial organelles. However, it is now clear that defects in immotile primary cilia, which have a variety of different sensory functions [44], can cause myriad inherited diseases that simultaneously involve several different organ systems and thus display pleiotropic phenotypes. These diseases range from severe developmental defects resulting in embryonic or perinatal lethality to diseases such as polycystic kidney disease (PKD), retinal degeneration, hepatic and pancreatic cysts, skeletal anomalies, brain malformations such as microcephaly and cerebellar dysplasia, and left–right axis defects. Ciliopathies are also associated with other types of lesions affecting the eye, central nervous system (CNS), liver, and pancreas.

The sensory functions of primary cilia depend on the coordinated trafficking and temporal localization of specific receptors and their associated signal transduction modules in the cilium. Primary cilia sense and transduce environmental signals via several signaling pathways, including HH, GPCR, WNT, receptor tyrosine kinase, and transforming growth factor β (TGFβ)/bone morphogenetic protein (BMP) signaling [8]. The central importance of these pathways in regulating key processes in development and tissue homeostasis account for the pleomorphic developmental disorders and diseases that accompany primary cilia defects [45]. The role of primary cilia in HH signaling is probably the best understood at this time. There are three major protein ligands in the HH system: SHH, Indian Hedgehog (IHH), and Desert Hedgehog (DHH). Of these, SHH signaling is critical to spatial patterning of the neuroepithelium, cellular identity in the CNS, axonal guidance, wiring of the neural network, and neuronal activity. Primary cilia defects in mice with mutations in SHH are associated with several defects in brain development, such as defective neural patterning, cerebellar hypoplasia, and defective hippocampal neurogenesis. IHH and DHH are both essential for normal craniofacial development, and mutations in several HH‐related ciliary proteins result in skeletal and craniofacial deformities [46].