Chapter 5 Modeling Ciliopathies: Primary Cilia in Development and Disease

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Abstract

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 information derived from the study of the ciliopathies and their animal models.

“This world, after all our science and sciences, is still a miracle; wonderful, inscrutable, magical and more, to whosoever will think of it.” (Thomas Carlyle)

Section snippets

The Human Ciliopathies

The term “ciliopathy” has been coined to describe a class of rare human genetic diseases whose etiologies lie in defective cilia. In vertebrates, cilia are present in nearly all organs and cell types; however, amongst invertebrates they are confined to the sensory neurons that sense chemical stimuli, changes in environment and even vibration (Evans et al., 2006). Cilia fall into two broad categories: those that are motile and those that are not. As the name would suggest, motile cilia and

Bardet-Biedl Syndrome

Bardet-Biedl syndrome (BBS) is a heterogeneous pleiotropic disorder inherited in a mainly recessive manner. Despite the growing list of syndromes now classified as a ciliopathy, it has been BBS that has led the quest to understand the pathomechanisms of this class of disease. Its clinical features include retinal degeneration, cognitive impairment, obesity, renal cystic disease, polydactyly, and occasionally situs inversus. It was these observations, in light of emerging evidence of the

Alström Syndrome

Alström syndrome (ALMS) is a rare recessive disorder that shows strong resemblance to BBS. It is characterized by cardinal features such as cone-rod dystrophy, neurosensory hearing loss, early-onset obesity, and insulin resistance leading to type 2 diabetes. A number of other features may also be present such as dilated cardiomyopathy, hepatic and urinary dysfunction, short stature, and male hypogonadism (Joy et al., 2007). It has been demonstrated that variable sensorineural hearing loss in

Polycystic Kidney Disease

The most commonly inherited PKDs are transmitted as autosomal-dominant (ADPKD) or autosomal-recessive (ARPKD) traits (Ibraghimov-Beskrovnaya and Bukanov, 2008). Although both forms of PKD initiate early in life, ARPKD rapidly progresses to kidney failure shortly after birth whereas ADPKD can take many years to reach end-stage renal disease (ESRD); typically by the fifth decade. Although both forms of the disease are characterized by the development and expansion of numerous fluid-filled cysts

Nephronophthisis

Nephronophthisis (NPHP) is an autosomal-recessive cystic renal condition characterized by corticomedullary clustering of cysts and tubulointerstitial fibrosis. In contrast to PKD where enlarged kidneys are a common diagnostic feature, the overall size of the kidney in NPHP is normal or diminished. Although, strictly speaking, NPHP describes a renal histopathology, ∼10% of cases also present with extrarenal manifestations that can be associated with other syndromes such as retinitis pigmentosa

Meckel Syndrome

The lethal autosomal-recessive Meckel syndrome (MKS) is characterized by renal cystic dysplasia with fibrotic changes in the liver, occipital encephalocoele or some other central nervous system malformation. Additionally, polydactyly is frequently reported and some patients have cleft palate, cardiac abnormalities, and incomplete development of genitalia and gonads (Dawe et al., 2007, Paavola et al., 1997, Salonen, 1984, Salonen and Paavola, 1998). Patients with MKS invariably die from

Joubert Syndrome

Joubert syndrome (JBTS) is an autosomal-recessive condition characterized by hypotonia, ataxia, severe psychomotor delay, oculomotor apraxia, and episodes of rapid breathing. Diagnosis may be supported by the neuroradiological hallmark referred to as the “molar tooth sign” (MTS), owing to horizontally oriented and thickened superior cerebellar peduncles and a deepened interpeduncular fossa combined with cerebellar vermis hypoplasia (Louie and Gleeson, 2005). The MTS has greatly enhanced the

Jeune Syndrome

Jeune asphyxiating thoracic dystrophy (JATD) is an autosomal-recessive chondrodysplasia. Affected children often die in the perinatal period owing to respiratory insufficiency that is a consequence of narrow and slender ribs and abnormal cage formation. Radiographical analysis can also indicate a shortening of the long bones and changes of the pelvic bones and the phalanges. There can be multiorgan involvement such as biliary dysgenesis with portal fibrosis and bile duct proliferation, renal

Oral–Facial–Digital Syndrome

Oral–facial–digital (OFD) type 1 syndrome is an X-linked-dominant disease characterized by malformations of oral cavity, face, and digits and by cystic kidneys. Facial features include hypertelorism, broad nasal bridge, buccal frenula, cleft palate, lobulated tongue, lingual hamartomas; in the hands and feet, brachydactyly, and polydactyly may be present. PKD is common and central nervous system malformations include corpus callosum agenesis, cerebellar abnormalities, and hydrocephalus, with

The Structure and Function of the Cilium

Historically, much of what we know of the structure and workings of the cilium/flagellum has come from a number of model organisms whose strengths are include both that they are amenable to genetic manipulation and relatively simple organisms, compared to mammalian models making them ideal for microscopic analysis. These include the unicellular green algae flagellate, Chlamydomonas reinhardtii, the ciliated protozoan, Tetrahymena, and the nematode worm, Caenorhabditis elegans. The finding that

Left–right determination

A fundamental question perplexing developmental biologists for decades concerned the mechanism that establishes LR asymmetry, almost universal amongst vertebrates. A failure to break symmetry during early development can lead to a randomization of subsequent body organs, referred to as situs inversus, which is a common ciliopathy phenotype LR asymmetry was first associated with cilia motility following observations of patients with a form of primary ciliary dyskinesia (PCD) known as

Therapies for Cystic Disease

Of all phenotypes seen within the ciliopathies, it is the renal pathologies that are the greatest contributor to morbidity and mortality in affected patients. As an example, in ADPKD, cyst growth can lead to dramatic increases in overall kidney mass; at times up to 20 kg (Germino and Somlo, 1993). Eventually, the size and number of cysts replace functional tissue and normal kidney filtration is impaired, resulting in ESRD in approximately 50% of patients. The only effective treatment currently

Concluding Remarks

Since the discovery of the cell by Robert Hooke (1663) and bacteria and protozoa by Anton van Leeuwenhoek (1673), the history of cell biology has been punctuated by epic advances. The cilium, that century-old object of curiosity, has recently enjoyed a rebirth, and with it has come astonishing biological revelations marking the next chapter in cellular history. Perhaps, unlike its forbearers, the rapidity of discoveries linked to the cilia is equally as remarkable and we owe these fortunes to

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