Alström Syndrome protein ALMS1 localizes to basal bodies of cochlear hair cells and regulates cilium-dependent planar cell polarity

SummaryThe molecular mechanisms by which cilia orientation is coordinated within and between multiciliated cells (MCCs) is not fully understood. By observing the orientation of basal bodies (BB) in MCCs of mouse oviducts, here, we show that Celsr1, a planar cell polarity (PCP) factor involved in tissue polarity regulation, is dispensable for determining BB orientation in individual cells, whereas CAMSAP3, a microtubule minus-end regulator, is critical for this process but not for PCP. MCCs exhibit a characteristic BB orientation and microtubule gradient along the tissue axis, and these intracellular polarities were maintained in the cells lacking Celsr1, although the intercellular coordination of the polarities was partly disrupted. On the other hand, CAMSAP3 regulated the assembly of microtubules interconnecting BBs by localizing at the BBs, and its mutation led to disruption of intracellular coordination of BB orientation, but not affecting PCP factor localization. Thus, both Celsr1 and CAMSAP3 are responsible for BB orientation but in distinct ways; and therefore, their cooperation should be critical for generating functional multiciliated tissues.

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Planar Cell Polarity Defects and Hearing Loss in Sperm-Associated Antigen 6 (Spag6)-Deficient Mice

AJP Cell Physiology ◽

10.1152/ajpcell.00166.2020 ◽

2020 ◽

Author(s):

Xiaofei Li ◽

Daogong Zhang ◽

Lei Xu ◽

Yuechen Han ◽

Wenwen Liu ◽

...

Keyword(s):

Hearing Loss ◽

Inner Ear ◽

Cell Polarity ◽

Planar Cell Polarity ◽

Structural Features ◽

Sensory Cells ◽

Basal Bodies ◽

Cellular Polarity ◽

Central Apparatus ◽

Deficient Mice

Spag6 encodes an axoneme central apparatus protein that is required for normal flagellar and cilia motility. Recent findings suggest that Spag6 also plays a role in ciliogenesis, orientation of cilia basal feet, and planar polarity. Sensory cells of the inner ear display unique structural features that underlie their mechanosensitivity. They represent a distinctive form of cellular polarity, known as planar cell polarity (PCP). However, a role for Spag6 in the inner ear has not yet been explored. In the present study, the function of Spag6 in the inner ear was examined using Spag6-deficient mice. Our results demonstrate hearing loss in the Spag6 mutants, associated with abnormalities in cellular patterning, cell shape, stereocilia bundles and basal bodies, as well as abnormally distributed Frizzled class receptor 6 (FZD6), suggesting that Spag6 participates in PCP regulation. Moreover, we found that the sub-apical microtubule meshwork was disrupted. Our observations suggest new functions for Spag6 in hearing and PCP in the inner ear.

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The Alström Syndrome Protein, ALMS1, Interacts with α-Actinin and Components of the Endosome Recycling Pathway

PLoS ONE ◽

10.1371/journal.pone.0037925 ◽

2012 ◽

Vol 7 (5) ◽

pp. e37925 ◽

Cited By ~ 47

Author(s):

Gayle B. Collin ◽

Jan D. Marshall ◽

Benjamin L. King ◽

Gabriella Milan ◽

Pietro Maffei ◽

...

Keyword(s):

Alström Syndrome ◽

Alstrom Syndrome ◽

Recycling Pathway ◽

Syndrome Protein

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alms1 mutant zebrafish do not show hair cell phenotypes seen in other cilia mutants

10.1101/2020.11.13.381954 ◽

2020 ◽

Author(s):

Lauren Parkinson ◽

Tamara M. Stawicki

Keyword(s):

Hearing Loss ◽

Hair Cell ◽

Hair Cells ◽

Intraflagellar Transport ◽

Cell Loss ◽

Cell Types ◽

Mutant Mice ◽

Alström Syndrome ◽

Metabolic Defects ◽

Alstrom Syndrome

ABSTRACTMultiple cilia-associated genes have been shown to affect hair cells in zebrafish (Danio rerio), including the human deafness gene dcdc2, the radial spoke gene rsph9, and multiple intraflagellar transport (IFT) and transition zone genes. Recently a zebrafish alms1 mutant was generated. The ALMS1 gene is the gene mutated in the ciliopathy Alström Syndrome a disease that causes hearing loss among other symptoms. The hearing loss seen in Alström Syndrome may be due in part to hair cell defects as Alms1 mutant mice show stereocilia polarity defects and a loss of hair cells. Hair cell loss is also seen in postmortem analysis of Alström patients. The zebrafish alms1 mutant has metabolic defects similar to those seen in Alström syndrome and Alms1 mutant mice. We wished to investigate if it also had hair cell defects. We, however, failed to find any hair cell related phenotypes in alms1 mutant zebrafish. They had normal lateral line hair cell numbers as both larvae and adults and normal kinocilia formation. They also showed grossly normal swimming behavior, response to vibrational stimuli, and FM1-43 loading. Mutants also showed a normal degree of sensitivity to both short-term neomycin and long-term gentamicin treatment. These results indicate that cilia-associated genes differentially affect different hair cell types.

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A role for the Alström syndrome protein, Alms1, in ciliogenesis and regulation of cellular quiescence in kidney proximal tubules

PLoS Genetics ◽

10.1371/journal.pgen.0030008.eor ◽

2005 ◽

Vol preprint (2006) ◽

pp. e8

Author(s):

Guochun Li ◽

Raquel Vega ◽

Keats Nelms ◽

Nicholas Gekakis ◽

Christopher Goodnow ◽

...

Keyword(s):

Proximal Tubules ◽

Alström Syndrome ◽

Cellular Quiescence ◽

Alstrom Syndrome ◽

Syndrome Protein ◽

Kidney Proximal Tubules

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Par3 is essential for the establishment of planar cell polarity of inner ear hair cells

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1816333116 ◽

2019 ◽

Vol 116 (11) ◽

pp. 4999-5008 ◽

Cited By ~ 11

Author(s):

Andre Landin Malt ◽

Zachary Dailey ◽

Julia Holbrook-Rasmussen ◽

Yuqiong Zheng ◽

Arielle Hogan ◽

...

Keyword(s):

Hair Cell ◽

Inner Ear ◽

Cell Polarity ◽

Hair Cells ◽

Planar Cell Polarity ◽

Tissue Level ◽

Hair Bundle ◽

Nucleotide Exchange ◽

Genetic Mosaic ◽

Pcp Signaling

In the inner ear sensory epithelia, stereociliary hair bundles atop sensory hair cells are mechanosensory apparatus with planar polarized structure and orientation. This is established during development by the concerted action of tissue-level, intercellular planar cell polarity (PCP) signaling and a hair cell-intrinsic, microtubule-mediated machinery. However, how various polarity signals are integrated during hair bundle morphogenesis is poorly understood. Here, we show that the conserved cell polarity protein Par3 is essential for planar polarization of hair cells. Par3 deletion in the inner ear disrupted cochlear outgrowth, hair bundle orientation, kinocilium positioning, and basal body planar polarity, accompanied by defects in the organization and cortical attachment of hair cell microtubules. Genetic mosaic analysis revealed that Par3 functions both cell-autonomously and cell-nonautonomously to regulate kinocilium positioning and hair bundle orientation. At the tissue level, intercellular PCP signaling regulates the asymmetric localization of Par3, which in turn maintains the asymmetric localization of the core PCP protein Vangl2. Mechanistically, Par3 interacts with and regulates the localization of Tiam1 and Trio, which are guanine nucleotide exchange factors (GEFs) for Rac, thereby stimulating Rac-Pak signaling. Finally, constitutively active Rac1 rescued the PCP defects in Par3-deficient cochleae. Thus, a Par3–GEF–Rac axis mediates both tissue-level and hair cell-intrinsic PCP signaling.

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