Vestibular hair cells in the inner ear encode head movements and mediate the sense of balance. These cells undergo cell death and replacement (turnover) throughout life in non-mammalian vertebrates. However, there is no definitive evidence that this process occurs in mammals. We used fate-mapping and other methods to demonstrate that utricular type II vestibular hair cells undergo turnover in adult mice under normal conditions. We found that supporting cells phagocytose both type I and II hair cells. Plp1-CreERT2-expressing supporting cells replace type II hair cells. Type I hair cells are not restored by Plp1-CreERT2-expressing supporting cells or by Atoh1-CreERTM-expressing type II hair cells. Destruction of hair cells causes supporting cells to generate 6 times as many type II hair cells compared to normal conditions. These findings expand our understanding of sensorineural plasticity in adult vestibular organs and further elucidate the roles that supporting cells serve during homeostasis and after injury.DOI: http://dx.doi.org/10.7554/eLife.18128.001

Utricles are vestibular sense organs that encode linear head movements. They are composed of a sensory epithelium with type I and type II hair cells and supporting cells, sitting atop connective tissue, through which vestibular nerves project. We characterized utricular Cre expression in 11 murine CreER lines using the ROSA26 reporter line and tamoxifen induction at 6 weeks of age. This characterization included Calbindin2, Fgfr3-iCreER, GFAP-A-CreER™, GFAP-B-CreER™, GLAST-CreER, Id2, Otoferlin, Parvalbumin, Prox1, Sox2, and Sox9-CreER. Otoferlin mice had inducible Cre activity specific to hair cells. GLAST-CreER, Id2, and Sox9-CreER had inducible Cre activity specific to supporting cells. Sox2 had inducible Cre activity in supporting cells and most type II hair cells. Parvalbumin mice had small numbers of labeled vestibular nerve afferents. Calbindin2 mice had labeling of most type II hair cells and some type I hair cells and supporting cells. Only rare (or no) tdTomato-positive cells were detected in utricles of Fgfr3-iCreER, GFAP-A-CreER™, GFAP-B-CreER™, and Prox1 mice. No Cre leakiness (tdTomato expression in the absence of tamoxifen) was observed in Otoferlin mice. A small degree of leakiness was seen in GLAST-CreER, Id2, Sox2, and Sox9-CreER lines. Calbindin2 mice had similar tdTomato expression with or without tamoxifen, indicating lack of inducible control under the conditions tested. In conclusion, 5 lines-GLAST-CreER, Id2, Otoferlin, Sox2, and Sox9-CreER-showed cell-selective, inducible Cre activity with little leakiness, providing new genetic tools for researchers studying the vestibular periphery.

Objective Autosomal‐dominant familial Alzheimer disease ( AD ) is caused by by variants in presenilin 1 ( PSEN 1 ), presenilin 2 ( PSEN 2 ), and amyloid precursor protein ( APP ). Previously, we reported a rare PSEN 2 frameshift variant in an early‐onset AD case ( PSEN 2 p.K115Efs*11). In this study, we characterize a second family with the same variant and analyze cellular transcripts from both patient fibroblasts and brain lysates. Methods We combined genomic, neuropathological, clinical, and molecular techniques to characterize the PSEN 2 K115Efs*11 variant in two families. Results Neuropathological and clinical evaluation confirmed the AD diagnosis in two individuals carrying the PSEN 2 K115Efs*11 variant. A truncated transcript from the variant allele is detectable in patient fibroblasts while levels of wild‐type PSEN 2 transcript and protein are reduced compared to controls. Functional studies to assess biological consequences of the variant demonstrated that PSEN 2 K115Efs*11 fibroblasts secrete less A β 1–40 compared to controls, indicating abnormal γ ‐secretase activity. Analysis of PSEN 2 transcript levels in brain tissue revealed alternatively spliced PSEN 2 products in patient brain as well as in sporadic AD and age‐matched control brain. Interpretation These data suggest that PSEN 2 K115Efs*11 is a likely pathogenic variant associated with AD . We uncovered novel PSEN 2 alternative transcripts in addition to previously reported PSEN 2 splice isoforms associated with sporadic AD . In the context of a frameshift, these alternative transcripts return to the canonical reading frame with potential to generate deleterious protein products. Our findings suggest novel potential mechanisms by which PSEN variants may influence AD pathogenesis, highlighting the complexity underlying genetic contribution to disease risk.

Dementing illnesses are progressive, neurodegenerative conditions most commonly occurring sporadically after age 65. A subset of dementia cases, however, are hereditary (Bekris et al., 2010) and have been shown to be caused by pathogenic variants in genes such as PSEN1, PSEN2, APP, GRN, and MAPT (Blue et al., 2018) and by C9orf72 GGGGCC hexanucleotide repeat expansions (Lee et al., 2014). Still, many familial cases remain unsolved by genetic testing and are not sufficiently explained by known risk alleles, such

Segmental progeroid syndromes are groups of genetic disorders with multiple features resembling accelerated aging. The International Registry of Werner Syndrome (Seattle, WA) recruits pedigrees of progeroid syndromes from all over the world. We identified two novel LMNA mutations, p.Asp300Gly in a patient from Myanmar, and p.Asn466Lys, in a patient from Greece. Both were referred to our Registry for the genetic diagnosis because of the accelerated aged-appearance and cardiac complications. LMNA mutations are the second most common genetic cause of progeroid syndromes after WRN mutations in our Registry. As the next generation sequencing becomes readily available, we expect to identify more cases of rare genetic diseases in the developing countries.

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