Ciliary proteins Bbs8 and Ift20 promote planar cell polarity in the cochlea

May-Simera, Helen; Petralia, Ronald S.; Montcouquiol, Mireille; Wang, Ya Xian; Szarama, Katherine B.; Liu, Yun; Lin, Weichun; Deans, Michael R.; Pazour, Gregory J.; Kelley, Matthew W.

doi:10.1242/dev.113696

Cited by 68 publications

(62 citation statements)

References 62 publications

(85 reference statements)

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“…These mice show several ciliopathy-related phenotypes including obesity and retinal degeneration (Kulaga et al, 2004; Mykytyn et al, 2004; Tadenev et al, 2011). They also show defective orientation of the sensory hair cells in the inner ear of the cochlea, a common failure found in PCP mutants (May-Simera et al, 2015; Ross et al, 2005). BBS4 null mice show partially penetrant embryonic lethality and all pups which develop to term are runts at birth (Kulaga et al, 2004; Mykytyn et al, 2004).…”

Section: Resultsmentioning

confidence: 98%

“…Thus it has been suggested that cilia act independently of, or downstream from, the PCP signalling pathway during cellular polarisation (Wallingford and Mitchell, 2011). However this interpretation is still controversial as a recent report showed a possible upstream function of cilia-related proteins to target a core PCP protein to the specific apical region of the sensory hair cells of the cochlea (May-Simera et al, 2015). In the lens fibres the cilia show distinct polarisation and this prompted us to speculate that cilia have a role in cellular polarisation (Sugiyama et al, 2011).…”

Section: Discussionmentioning

confidence: 99%

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Non-essential role for cilia in coordinating precise alignment of lens fibres

Sugiyama

Shelley

Yoder

et al. 2016

Mechanisms of Development

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The primary cilium, a microtubule-based organelle found in most cells, is a centre for mechano-sensing fluid movement and cellular signalling, notably through the Hedgehog pathway. We recently found that each lens fibre cell has an apically situated primary cilium that is polarised to the side of the cell facing the anterior pole of the lens. The direction of polarity is similar in neighbouring cells so that in the global view, lens fibres exhibit planar cell polarity (PCP) along the equatorial-anterior polar axis. Ciliogenesis has been associated with the establishment of PCP, although the exact relationship between PCP and the role of cilia is still controversial. To test the hypothesis that the primary cilia have a role in coordinating the precise alignment/orientation of the fibre cells, IFT88, a key component of the intraflagellar transport (IFT) complex, was removed specifically from the lens at different developmental stages using several lens-specific Cre-expressing mouse lines (MLR10- and LR-Cre). Irrespective of which Cre-line was adopted, both demonstrated that in IFT88-depleted cells, the ciliary axoneme was absent or substantially shortened, confirming the disruption of primary cilia formation. However no obvious histological defects were detected even when IFT88 was removed from the lens placode as early as E9.5. Specifically, the lens fibres aligned/oriented towards the poles to form the characteristic Y-shaped sutures as normal. Consistent with this, in primary lens epithelial explants prepared from these conditional knockout mouse lenses, the basal bodies still showed polarised localisation at the apical surface of elongating cells upon FGF-induced fibre differentiation. We further investigated the lens phenotype in knockouts of Bardet–Biedl Syndrome (BBS) proteins 4 and 8, the components of the BBSome complex which modulate ciliary function. In these BBS4 and 8 knockout lenses, again we found the pattern of the anterior sutures formed by the apical tips of elongating/migrating fibres were comparable to the control lenses. Taken together, these results indicate that primary cilia do not play an essential role in the precise cellular alignment/orientation of fibre cells. Thus, it appears that in the lens cilia are not required to establish PCP.

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Section: Resultsmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 99%

Non-essential role for cilia in coordinating precise alignment of lens fibres

Sugiyama

Shelley

Yoder

et al. 2016

Mechanisms of Development

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“…Eliminating kinocilia mediated apical reorganization results in circular polarized hair cells (Jones et al, 2008). Beyond the kinocilium as a signaling center, the apical acentric polarity development relies on several regulatory factors, such as LGN and Gαi (Tarchini et al, 2016) and Bbs8 and Ift20 (May-Simera et al, 2015) to eliminate microvilli and move the kinocilium into an acentric position and regulate the height and distribution of stereocilia to properly polarize hair cells. The end product of this incompletely understood process (Lu and Sipe, 2016; Schüler et al, 2013) is a highly polarized cell that allows mechanical stimuli to exert changes on the cell’s resting potential depending on the direction of the stimulation (Fig.…”

Section: Introductionmentioning

confidence: 99%

“…Hair cells show variable stereociliary diameters that clearly are affected by bHLH genes (Jahan et al, 2013, 2015b), but also show the unique stereocilia arrangements of inner and outer hair cells that apparently evolved out of the much simpler stereocilia bundle found in ancestral hair cells of the vestibular type (Lewis et al, 1985). When and how factors that coordinate polarity of hair cells across sensory epithelia (May-Simera et al, 2015) evolved is unclear. Thus, while some connections between Atoh1 level of expression and some of the downstream factors needed for the apical development of the stereocilia bundle are likely (Taura et al, 2016), we do not yet understand how vestibular and cochlear hair cells molecularly evolved their unique stereocilia organization and loss of a kinocilium.…”

Section: Introductionmentioning

confidence: 99%

Gene, cell, and organ multiplication drives inner ear evolution

Fritzsch

Elliott

2017

Developmental Biology

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We review the development and evolution of the ear neurosensory cells, the aggregation of neurosensory cells into an otic placode, the evolution of novel neurosensory structures dedicated to hearing and the evolution of novel nuclei and their input dedicated to processing those novel auditory stimuli. The evolution of the apparently novel auditory system lies in duplication and diversification of cell fate transcription regulation that allows variation at the cellular level [transforming a single neurosensory cell into a sensory cell connected to its targets by a sensory neuron as well as diversifying hair cells], organ level [duplication of organ development followed by diversification and novel stimulus acquisition] and brain nuclear level [multiplication of transcription factors to regulate various neuron and neuron aggregate fate to transform the spinal cord into the unique hindbrain organization]. Tying cell fate changes driven by bHLH and other transcription factors into cell and organ changes is at the moment tentative as not all relevant factors are known and their gene regulatory network is only rudimentary understood. Future research can use the blueprint proposed here to provide both the deeper molecular evolutionary understanding as well as a more detailed appreciation of developmental networks. This understanding can reveal how an auditory system evolved through transformation of existing cell fate determining networks and thus how neurosensory evolution occurred through molecular changes affecting cell fate decision processes. Appreciating the evolutionary cascade of developmental program changes could allow identifying essential steps needed to restore cells and organs in the future.

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“…BBS8 was recently shown play a role in establishing planar cell polarity and orientation of cilia in epithelial cells (22). To date, six mutations in the BBS8 gene have been linked to classical BBS (18,23,24).…”

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confidence: 99%

Alternative Splicing Shapes the Phenotype of a Mutation in BBS8 To Cause Nonsyndromic Retinitis Pigmentosa

Murphy

Singh

Kolandaivelu

et al. 2015

Molecular and Cellular Biology

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Bardet-Biedl syndrome (BBS) is a genetic disorder affecting multiple systems and organs in the body. Several mutations in genes associated with BBS affect only photoreceptor cells and cause nonsyndromic retinitis pigmentosa (RP), raising the issue of why certain mutations manifest as a systemic disorder whereas other changes in the same gene affect only a specific cell type. Here, we show that cell-type-specific alternative splicing is responsible for confining the phenotype of the A-to-G substitution in the 3= splice site of BBS8 exon 2A (IVS1-2A>G mutation) in the BBS8 gene to photoreceptor cells. The IVS1-2A>G mutation leads to missplicing of BBS8 exon 2A, producing a frameshift in the BBS8 reading frame and thus eliminating the protein specifically in photoreceptor cells. Cell types other than photoreceptors skip exon 2A from the mature BBS8 transcript, which renders them immune to the mutation. We also show that the splicing of Bbs8 exon 2A in photoreceptors is directed exclusively by redundant splicing enhancers located in the adjacent introns. These intronic sequences are sufficient for photoreceptor-cell-specific splicing of heterologous exons, including an exon with a randomized sequence. The BBSome is a multiprotein complex that is thought be required for the transport of proteins in and out of the cilia. The BBSome interacts with intraflagellar transport A (IFT-A) and IFT-B complexes and promotes the assembly of the IFT machinery (1-7). Several proteins, such as the G-protein-coupled receptors Smo, Sstr3, Mchr1, and Vipr2, depend on the BBSome for their ciliary transport, suggesting a possible role for the BBSome as an adapter that connects the IFT complex to its cargo in primary cilia (2,8,9). Mutations in genes that encode BBSome components and proteins associated with the BBSome are linked to systemic Bardet-Biedl syndrome (BBS). BBS is an autosomal recessive ciliopathy caused by defects in the BBSome that disrupt the normal ciliary function throughout the body. BBS symptoms include retinitis pigmentosa (RP), skeletal malformations, mental retardation, obesity, hearing impairment, shortened limbs, polydactyly, and kidney cysts (10, 11). In photoreceptor cells, BBSome deficiency leads to defects in rod outer-segment formation and localization of rod opsin and, ultimately, photoreceptor cell death (10-13). The severity of the BBS symptoms can vary considerably due to the nature of the mutation and the genetic background. Interestingly, phenotypes of different mutations in the same gene can range from a classical BBS that affects multiple systems to nonsyndromic RP, where the phenotype is limited to loss of photoreceptor function. For example, the ARL6 (BBS3) A89V, BBS1 M390R, and BBS8 IVS1-2AϾG mutations cause nonsyndromic RP, while several other mutations in the same genes manifest as classical BBS, presenting additional symptoms such as obesity, hearing impairment, polydactyly, and mental retardation in addition to the loss of vision (7,(14)(15)(16)(17)(18)(19). The existence of BBSome mutations th...

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Ciliary proteins Bbs8 and Ift20 promote planar cell polarity in the cochlea

Cited by 68 publications

References 62 publications

Non-essential role for cilia in coordinating precise alignment of lens fibres

Non-essential role for cilia in coordinating precise alignment of lens fibres

Gene, cell, and organ multiplication drives inner ear evolution

Alternative Splicing Shapes the Phenotype of a Mutation in BBS8 To Cause Nonsyndromic Retinitis Pigmentosa

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