LMO7 deficiency reveals the significance of the cuticular plate for hearing function

Du, Ting-Ting; Dewey, James B.; Wagner, Elizabeth; Cui, Runjia; Heo, Jun; Park, Jeong Jin; Francis, Shimon P.; Perez‐Reyes, Edward; Guillot, Stacey J.; Sherman, Nicholas E.; Xu, Wenhao; Oghalai, John S.; Kachar, Bechara; Shin, Jung-Bum

doi:10.1038/s41467-019-09074-4

Cited by 40 publications

(28 citation statements)

References 63 publications

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“…These were further supported by the observations that MAP1B deficiency did not affect the morphologies in middle turns, apex, and basal turns of cochlea of mice, in contrast with those in mice bearing other deafness-causing gene mutations such as CDC14A (46)(47)(48). Strikingly, MAP1B deficiency in the mice cochlea altered the morphology and function of SGNs rather than inner hair cells or outer hair cells in other deafness genes such as LMO7 (48). This was supported by abnormal morphology of SGNs, including shortened neurite lengths, in the Map1b-KO mice.…”

Section: Discussionsupporting

confidence: 52%

“…These data suggest that Map1b deletion did not affect the function of hair cells but may alter the function of spiral ganglia neurons. These were further supported by the observations that MAP1B deficiency did not affect the morphologies in middle turns, apex, and basal turns of cochlea of mice, in contrast with those in mice bearing other deafness-causing gene mutations such as CDC14A (46)(47)(48). Strikingly, MAP1B deficiency in the mice cochlea altered the morphology and function of SGNs rather than inner hair cells or outer hair cells in other deafness genes such as LMO7 (48).…”

Section: Discussionmentioning

confidence: 56%

See 1 more Smart Citation

Mutations of MAP1B encoding a microtubule-associated phosphoprotein cause sensorineural hearing loss

Cui¹,

Zheng²,

Zhao³

et al. 2020

JCI Insight

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The pathophysiology underlying spiral ganglion cell defect–induced deafness remains elusive. Using the whole exome sequencing approach, in combination with functional assays and a mouse disease model, we identified the potentially novel deafness-causative MAP1B gene encoding a highly conserved microtubule-associated protein. Three novel heterozygous MAP1B mutations (c.4198A>G, p.1400S>G; c.2768T>C, p.923I>T; c.5512T>C, p.1838F>L) were cosegregated with autosomal dominant inheritance of nonsyndromic sensorineural hearing loss in 3 unrelated Chinese families. Here, we show that MAP1B is highly expressed in the spiral ganglion neurons in the mouse cochlea. Using otic sensory neuron–like cells, generated by pluripotent stem cells from patients carrying the MAP1B mutation and control subject, we demonstrated that the p.1400S>G mutation caused the reduced levels and deficient phosphorylation of MAP1B, which are involved in the microtubule stability and dynamics. Strikingly, otic sensory neuron–like cells exhibited disturbed dynamics of microtubules, axonal elongation, and defects in electrophysiological properties. Dysfunctions of these derived otic sensory neuron–like cells were rescued by genetically correcting MAP1B mutation using CRISPR/Cas9 technology. Involvement of MAP1B in hearing was confirmed by audiometric evaluation of Map1b heterozygous KO mice. These mutant mice displayed late-onset progressive sensorineural hearing loss that was more pronounced in the high frequencies. The spiral ganglion neurons isolated from Map1b mutant mice exhibited the deficient phosphorylation and disturbed dynamics of microtubules. Map1b deficiency yielded defects in the morphology and electrophysiology of spiral ganglion neurons, but it did not affect the morphologies of cochlea in mice. Therefore, our data demonstrate that dysfunctions of spiral ganglion neurons induced by MAP1B deficiency caused hearing loss.

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Section: Discussionsupporting

confidence: 52%

Section: Discussionmentioning

confidence: 56%

Mutations of MAP1B encoding a microtubule-associated phosphoprotein cause sensorineural hearing loss

Cui¹,

Zheng²,

Zhao³

et al. 2020

JCI Insight

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“…Specifically, as we revealed in zebrafish, SMPX is embedded in the cuticular plate (CP) of the hair cell, an actin-based specialized structure located underneath the apical plasma membrane [ 4 ], which profoundly influences mechanotransduction or the ability of hair cells to convert a mechanical stimulus ( i.e. , an acoustic wave) into a neural signal ([ 5 ] and references therein). Indeed, the CP is the anchoring region for the actin-containing rootlets of the stereocilia, which, in turn, form the sensory bundle of the vertebrate inner ear hair cells that bends under mechanical stimuli.…”

Section: Introductionmentioning

confidence: 99%

Inner Ear and Muscle Developmental Defects in Smpx-Deficient Zebrafish Embryos

Ghilardi

Diana

Bacchetta

et al. 2021

IJMS

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The last decade has witnessed the identification of several families affected by hereditary non-syndromic hearing loss (NSHL) caused by mutations in the SMPX gene and the loss of function has been suggested as the underlying mechanism. In the attempt to confirm this hypothesis we generated an Smpx-deficient zebrafish model, pointing out its crucial role in proper inner ear development. Indeed, a marked decrease in the number of kinocilia together with structural alterations of the stereocilia and the kinocilium itself in the hair cells of the inner ear were observed. We also report the impairment of the mechanotransduction by the hair cells, making SMPX a potential key player in the construction of the machinery necessary for sound detection. This wealth of evidence provides the first possible explanation for hearing loss in SMPX-mutated patients. Additionally, we observed a clear muscular phenotype consisting of the defective organization and functioning of muscle fibers, strongly suggesting a potential role for the protein in the development of muscle fibers. This piece of evidence highlights the need for more in-depth analyses in search for possible correlations between SMPX mutations and muscular disorders in humans, thus potentially turning this non-syndromic hearing loss-associated gene into the genetic cause of dysfunctions characterized by more than one symptom, making SMPX a novel syndromic gene.

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“…Last year, another group discovered that LMO7 is specifically localized in the cuticular plate and the cell junction. LMO7 knockout mice suffer multiple cuticular plate deficiencies, including reduced filamentous actin density and abnormal stereocilia rootlets ( Du et al, 2019 ). The elevated levels of LMO7, also known as PCD1, have been reported in PC ( Kang et al, 2000 ).…”

Section: Introductionmentioning

confidence: 99%

LMO7 as an Unrecognized Factor Promoting Pancreatic Cancer Progression and Metastasis

Liu

Hao

Zhou

et al. 2021

Front. Cell Dev. Biol.

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Pancreatic cancer (PC) is one of the most lethal human malignancies without effective treatment. In an effort to discover key genes and molecular pathways underlying PC growth, we have identified LIM domain only 7 (LMO7) as an under-investigated molecule, which highly expresses in primary and metastatic human and mouse PC with the potential of impacting PC tumorigenesis and metastasis. Using genetic methods with siRNA, shRNA, and CRISPR-Cas9, we have successfully generated stable mouse PC cells with LMO7 knockdown or knockout. Using these cells with loss of LMO7 function, we have demonstrated that intrinsic LMO7 defect significantly suppresses PC cell proliferation, anchorage-free colony formation, and mobility in vitro and slows orthotopic PC tumor growth and metastasis in vivo. Mechanistic studies demonstrated that loss of LMO7 function causes PC cell-cycle arrest and apoptosis. These data indicate that LMO7 functions as an independent and unrecognized druggable factor significantly impacting PC growth and metastasis, which could be harnessed for developing a new targeted therapy for PC.

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LMO7 deficiency reveals the significance of the cuticular plate for hearing function

Cited by 40 publications

References 63 publications

Mutations of MAP1B encoding a microtubule-associated phosphoprotein cause sensorineural hearing loss

Mutations of MAP1B encoding a microtubule-associated phosphoprotein cause sensorineural hearing loss

Inner Ear and Muscle Developmental Defects in Smpx-Deficient Zebrafish Embryos

LMO7 as an Unrecognized Factor Promoting Pancreatic Cancer Progression and Metastasis

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