The Oak Ridge Polycystic Kidney mouse: Modeling ciliopathies of mice and men

Lehman, Jonathan M.; Michaud, Edward J.; Schoeb, Trenton R.; Son, Yeşim Aydın; Miller, M.K.; Yoder, Bradley K.

doi:10.1002/dvdy.21515

Cited by 115 publications

(111 citation statements)

References 94 publications

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“…The IFT88 protein is a component of the IFT, the bidirectional movement of particles between the tip and the base of the cilium required for cilia assembly and maintenance first described in Chlamydomonas (23). The hypomorphic Ift88 allele in the Tg737 orpk mouse leads to cilia that are stunted and malformed, but not completely abolished, thus allowing these homozygous mutants to survive within the weaning period (24). In contrast, mice that are heterozygous for this mutation appear indistinguishable from wild-type littermates (25).…”

Section: Resultsmentioning

confidence: 99%

Primary cilia dynamics instruct tissue patterning and repair of corneal endothelium

Blitzer

Panagis

Gusella

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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Primary cilia are required for several signaling pathways, but their function in cellular morphogenesis is poorly understood. Here we show that emergence of an hexagonal cellular pattern during development of the corneal endothelium (CE), a monolayer of neural crest-derived cells that maintains corneal transparency, depends on a precise temporal control of assembly of primary cilia that subsequently disassemble in adult corneal endothelial cells (CECs). However, cilia reassembly occurs rapidly in response to an in vivo mechanical injury and precedes basal body polarization and cellular elongation in mature CECs neighboring the wound. In contrast, CE from hypomorphic IFT88 mutants (Tg737 orpk ) or following in vivo lentiviral-mediated IFT88 knockdown display dysfunctional cilia and show disorganized patterning, mislocalization of junctional markers, and accumulation of cytoplasmic acetylated tubulin. Our results indicate an active role of cilia in orchestrating coordinated morphogenesis of CECs during development and repair and define the murine CE as a powerful in vivo system to study ciliary-based cellular dynamics. intraflagellar transport | eye development | ciliary length | microtubules

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Section: Resultsmentioning

confidence: 99%

Primary cilia dynamics instruct tissue patterning and repair of corneal endothelium

Blitzer

Panagis

Gusella

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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“…IFT88 is mutated in the Oak Ridge Polycystic Kidney (ORPK) mouse model for autosomal recessive polycystic kidney disease (Moyer et al , 1994; Lehman et al , 2008) and has since then be used extensively to uncover ciliary involvement in a plethora of processes such as skeletal patterning (Zhang et al , 2003), photoreceptor assembly and maintenance (Pazour et al , 2002), and more (reviewed in Lehman et al , 2008). However, no clear molecular function has so far been assigned to the IFT88 protein.…”

Section: Discussionmentioning

confidence: 99%

Intraflagellar transport proteins 172, 80, 57, 54, 38, and 20 form a stable tubulin‐binding IFT‐B2 complex

et al. 2016

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Intraflagellar transport (IFT) relies on the IFT complex and is required for ciliogenesis. The IFT‐B complex consists of 9–10 stably associated core subunits and six “peripheral” subunits that were shown to dissociate from the core structure at moderate salt concentration. We purified the six “peripheral” IFT‐B subunits of Chlamydomonas reinhardtii as recombinant proteins and show that they form a stable complex independently of the IFT‐B core. We suggest a nomenclature of IFT‐B1 (core) and IFT‐B2 (peripheral) for the two IFT‐B subcomplexes. We demonstrate that IFT88, together with the N‐terminal domain of IFT52, is necessary to bridge the interaction between IFT‐B1 and B2. The crystal structure of IFT52N reveals highly conserved residues critical for IFT‐B1/IFT‐B2 complex formation. Furthermore, we show that of the three IFT‐B2 subunits containing a calponin homology (CH) domain (IFT38, 54, and 57), only IFT54 binds αβ‐tubulin as a potential IFT cargo, whereas the CH domains of IFT38 and IFT57 mediate the interaction with IFT80 and IFT172, respectively. Crystal structures of IFT54 CH domains reveal that tubulin binding is mediated by basic surface‐exposed residues.

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“…Primary cilia are present on most cell types in the skin (Elofsson et al, 1984;Lehman et al, 2009;Lehman et al, 2008;Wandel et al, 1984;Warfvinge and Elofsson, 1988), yet their functional importance in the morphogenesis and maintenance of the skin and follicle is only now being investigated. Loss of dermal cilia results in follicular arrest due to attenuated Hh signaling (Lehman et al,…”

Section: Discussionmentioning

confidence: 99%

Role of epidermal primary cilia in the homeostasis of skin and hair follicles

et al. 2011

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SUMMARYSkin and hair follicle morphogenesis and homeostasis require the integration of multiple signaling pathways, including Hedgehog (Hh) and Wingless (Wnt), and oriented cell divisions, all of which have been associated with primary cilia. Although studies have shown that disrupting dermal cilia causes follicular arrest and attenuated Hh signaling, little is known about the role of epidermal cilia. Here, epidermal cilia function was analyzed using conditional alleles of the ciliogenic genes Ift88 and Kif3a. At birth, epidermal cilia mutants appeared normal, but developed basaloid hyperplasia and ingrowths into the dermis of the ventrum with age. In addition, follicles in the tail were disorganized and had excess sebaceous gland lobules. Epidermal cilia mutants displayed fewer long-term label-retaining cells, suggesting altered stem cell homeostasis. Abnormal proliferation and differentiation were evident from lineage-tracing studies and showed an expansion of follicular cells into the interfollicular epidermis, as is seen during wound repair. These phenotypes were not associated with changes in canonical Wnt activity or oriented cell division. However, nuclear accumulation of the DNp63 transcription factor, which is involved in stratification, keratinocyte differentiation and wound repair, was increased, whereas the Hh pathway was repressed. Intriguingly, the phenotypes were not typical of those associated with loss of Hh signaling but exhibited similarities with those of mice in which DNp63 is overexpressed in the epidermis. Collectively, these data indicate that epidermal primary cilia may function in stress responses and epidermal homeostasis involving pathways other than those typically associated with primary cilia.

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The Oak Ridge Polycystic Kidney mouse: Modeling ciliopathies of mice and men

Cited by 115 publications

References 94 publications

Primary cilia dynamics instruct tissue patterning and repair of corneal endothelium

Primary cilia dynamics instruct tissue patterning and repair of corneal endothelium

Intraflagellar transport proteins 172, 80, 57, 54, 38, and 20 form a stable tubulin‐binding IFT‐B2 complex

Role of epidermal primary cilia in the homeostasis of skin and hair follicles

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