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PMID:23533177

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Citation

Sipe, CW, Liu, L, Lee, J, Grimsley-Myers, C and Lu, X (2013) Lis1 mediates planar polarity of auditory hair cells through regulation of microtubule organization. Development 140:1785-95

Abstract

The V-shaped hair bundles atop auditory hair cells and their uniform orientation are manifestations of epithelial planar cell polarity (PCP) required for proper perception of sound. PCP is regulated at the tissue level by a conserved core Wnt/PCP pathway. However, the hair cell-intrinsic polarity machinery is poorly understood. Recent findings implicate hair cell microtubules in planar polarization of hair cells. To elucidate the microtubule-mediated polarity pathway, we analyzed Lis1 function in the auditory sensory epithelium in the mouse. We show that conditional deletion of Lis1 in developing hair cells causes defects in cytoplasmic dynein and microtubule organization, resulting in planar polarity defects without overt effects on the core PCP pathway. Lis1 ablation during embryonic development results in defects in hair bundle morphology and orientation, cellular organization and junctional nectin localization. We present evidence that Lis1 regulates localized Rac-PAK signaling in embryonic hair cells, probably through microtubule-associated Tiam1, a guanine nucleotide exchange factor for Rac. Lis1 ablation in postnatal hair cells significantly disrupts centrosome anchoring and the normal V-shape of hair bundles, accompanied by defects in the pericentriolar matrix and microtubule organization. Lis1 is also required for proper positioning of the Golgi complex and mitochondria as well as for hair cell survival. Together, our results demonstrate that Lis1 mediates the planar polarity of hair cells through regulation of microtubule organization downstream of the tissue polarity pathway.

Links

PubMed Online version:10.1242/dev.089763

Keywords


Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

MOUSE:NECT2

located_in

GO:0044291: cell-cell contact zone

ECO:0000314: direct assay evidence used in manual assertion

C

  • part_of:(CL:0000589)
  • part_of:(EMAPA:19061)

Seeded From UniProt

complete

MOUSE:RAC1

located_in

GO:0000242: pericentriolar material

ECO:0000314: direct assay evidence used in manual assertion

C

  • part_of:(EMAPA:17597)
  • part_of:(CL:0000589)

Seeded From UniProt

complete

MOUSE:RAC1

located_in

GO:0060091: kinocilium

ECO:0000314: direct assay evidence used in manual assertion

C

  • part_of:(EMAPA:17597)
  • part_of:(CL:0000589)

Seeded From UniProt

complete

MOUSE:LIS1

located_in

GO:0032420: stereocilium

ECO:0000314: direct assay evidence used in manual assertion

C

  • part_of:(EMAPA:17597)
  • part_of:(CL:0000589)

Seeded From UniProt

complete

MOUSE:TIAM1

enables

GO:0008017: microtubule binding

ECO:0000314: direct assay evidence used in manual assertion

F

  • occurs_in:(CL:0000589)
  • occurs_in:(EMAPA:19061)

Seeded From UniProt

complete

MOUSE:TIAM1

located_in

GO:0000242: pericentriolar material

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:TIAM1

located_in

GO:0060091: kinocilium

ECO:0000314: direct assay evidence used in manual assertion

C

  • part_of:(EMAPA:17597)
  • part_of:(CL:0000589)

Seeded From UniProt

complete

MOUSE:DVL2

located_in

GO:0016328: lateral plasma membrane

ECO:0000314: direct assay evidence used in manual assertion

C

  • part_of:(EMAPA:17597)
  • part_of:(CL:0000589)

Seeded From UniProt

complete

MOUSE:NECT1

located_in

GO:0044291: cell-cell contact zone

ECO:0000314: direct assay evidence used in manual assertion

C

  • part_of:(CL:0000589)
  • part_of:(EMAPA:19061)

Seeded From UniProt

complete

MOUSE:NECT3

located_in

GO:0044291: cell-cell contact zone

ECO:0000314: direct assay evidence used in manual assertion

C

  • part_of:(CL:0000589)
  • part_of:(EMAPA:19061)

Seeded From UniProt

complete

MOUSE:PCM1

located_in

GO:0000242: pericentriolar material

ECO:0000314: direct assay evidence used in manual assertion

C

  • part_of:(EMAPA:17597)
  • part_of:(CL:0000589)

Seeded From UniProt

complete

MOUSE:LIS1

GO:0090176: microtubule cytoskeleton organization involved in establishment of planar polarity

ECO:0000315:

P

Figure 2

complete
CACAO 7252

MOUSE:LIS1

GO:0042249: establishment of planar polarity of embryonic epithelium

ECO:0000315:

P

Figure 2

complete
CACAO 7253

MOUSE:LIS1

GO:0070507: regulation of microtubule cytoskeleton organization

ECO:0000315:

P

Figure 2 & 7.

complete
CACAO 7254

MOUSE:LIS1

GO:0060117: auditory receptor cell development

ECO:0000315:

P

Fig 3C,D. "Moreover, the apical surfaces of both hair cells and supporting cells in Lis1cKO-early cochleae were misshapen. Many hair cells adopted an oblong or irregular shape and the evenly spaced ‘hourglass’ shape of supporting cell apical domains was frequently jumbled and distorted (Fig. 3B)... the Lis1cKO-early sensory epithelium was disorganized, with hair cell nuclei frequently found at varying distances from the luminal surface (Fig. 3D). And Fig 8.

complete
CACAO 7255

MOUSE:LIS1

GO:0040019: positive regulation of embryonic development

ECO:0000315:

P

Figure 2

complete
CACAO 7256

MOUSE:LIS1

GO:0051130: positive regulation of cellular component organization

ECO:0000315:

P

Figure 3 - "Lis1 regulates cellular organization and junctional nectin localization in the organ of Corti"

complete
CACAO 7257

MOUSE:LIS1

GO:0090102: cochlea development

ECO:0000315:

P

Figure 3 - "Lis1 regulates cellular organization and junctional nectin localization in the organ of Corti."

complete
CACAO 7258

MOUSE:LIS1

involved_in

GO:0042249: establishment of planar polarity of embryonic epithelium

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:LIS1

involved_in

GO:0090102: cochlea development

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:LIS1

involved_in

GO:0051130: positive regulation of cellular component organization

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:LIS1

involved_in

GO:0040019: positive regulation of embryonic development

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:LIS1

involved_in

GO:0060117: auditory receptor cell development

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:LIS1

involved_in

GO:0070507: regulation of microtubule cytoskeleton organization

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:LIS1

involved_in

GO:0090176: microtubule cytoskeleton organization involved in establishment of planar polarity

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:LIS1

acts_upstream_of_or_within

GO:0051661: maintenance of centrosome location

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:2384060

P

  • occurs_in:(CL:0000589)
  • occurs_in:(EMAPA:19061)

Seeded From UniProt

complete

MOUSE:LIS1

part_of

GO:0032420: stereocilium

ECO:0000314: direct assay evidence used in manual assertion

C

  • part_of:(CL:0000589)
  • part_of:(EMAPA:17597)

Seeded From UniProt

complete

MOUSE:DVL2

part_of

GO:0016328: lateral plasma membrane

ECO:0000314: direct assay evidence used in manual assertion

C

  • part_of:(CL:0000589)
  • part_of:(EMAPA:17597)

Seeded From UniProt

complete

MOUSE:RAC1

part_of

GO:0000242: pericentriolar material

ECO:0000314: direct assay evidence used in manual assertion

C

  • part_of:(CL:0000589)
  • part_of:(EMAPA:17597)

Seeded From UniProt

complete

MOUSE:RAC1

part_of

GO:0060091: kinocilium

ECO:0000314: direct assay evidence used in manual assertion

C

  • part_of:(CL:0000589)
  • part_of:(EMAPA:17597)

Seeded From UniProt

complete


See also

References

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