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https://www.readbyqxmd.com/read/29553487/sox2-haploinsufficiency-primes-regeneration-and-wnt-responsiveness-in-the-mouse-cochlea
#1
Patrick J Atkinson, Yaodong Dong, Shuping Gu, Wenwen Liu, Elvis Huarcaya Najarro, Tomokatsu Udagawa, Alan G Cheng
During development, Sox2 is indispensable for cell division and differentiation, yet its roles in regenerating tissues are less clear. Here, we used combinations of transgenic mouse models to reveal that Sox2 haploinsufficiency (Sox2haplo) increases rather than impairs cochlear regeneration in vivo. Sox2haplo cochleae had delayed terminal mitosis and ectopic sensory cells, yet normal auditory function. Sox2haplo amplified and expanded domains of damage-induced Atoh1+ transitional cell formation in neonatal cochlea...
March 19, 2018: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/29548943/multiple-zebrafish-atoh1-genes-specify-a-diversity-of-neuronal-types-in-the-zebrafish-cerebellum
#2
Chelsea U Kidwell, Chen-Ying Su, Masahiko Hibi, Cecilia B Moens
A single Atoh1 basic-helix-loop-helix transcription factor specifies multiple neuron types in the mammalian cerebellum and anterior hindbrain. The zebrafish genome encodes three paralagous atoh1 genes whose functions in cerebellum and anterior hindbrain development we explore here. With use of a transgenic reporter, we report that zebrafish atoh1c-expressing cells are organized in two distinct domains that are separated both by space and developmental time. An early isthmic expression domain gives rise to an extracerebellar population in rhombomere 1 and an upper rhombic lip domain gives rise to granule cell progenitors that migrate to populate all four granule cell territories of the fish cerebellum...
March 13, 2018: Developmental Biology
https://www.readbyqxmd.com/read/29397531/a-simplified-method-for-generating-purkinje-cells-from-human-induced-pluripotent-stem-cells
#3
Lauren M Watson, Maggie M K Wong, Jane Vowles, Sally A Cowley, Esther B E Becker
The establishment of a reliable model for the study of Purkinje cells in vitro is of particular importance, given their central role in cerebellar function and pathology. Recent advances in induced pluripotent stem cell (iPSC) technology offer the opportunity to generate multiple neuronal subtypes for study in vitro. However, to date, only a handful of studies have generated Purkinje cells from human pluripotent stem cells, with most of these protocols proving challenging to reproduce. Here, we describe a simplified method for the reproducible generation of Purkinje cells from human iPSCs...
February 3, 2018: Cerebellum
https://www.readbyqxmd.com/read/29336137/-in-vitro-differentiation-of-human-bone-marrow-mesenchymal-stem-cells-to-hair-cells-using-growth-factors
#4
Mohammad-Reza Mahmoudian-Sani, Morteza Hashemzadeh-Chaleshtori, Mohammad-Saeid Jami, Massoud Saidijam
OBJECTIVE: In this study, we attempted to differentiated human bone marrow-derived mesenchymal stem cells (hBMSCs) to auditory hair cells using growth factors. METHODS: Retinoic acid (RA), basic fibroblast growth factor (bFGF), and epidermal growth factor (EGF) were added to hBMSCs cell culture medium. The cells were evaluated morphologically and the expression of SOX2, POU4F3, MYO7A, and Calretinin at mRNA level and ATOH1 mRNA and protein expression. RESULTS: After treatment with the growth factors, the morphology of the cells did not change, but evaluation of gene expression at the mRNA level increased the expression of the ATOH1, SOX2, and POU4F3 markers...
December 1, 2017: International Tinnitus Journal
https://www.readbyqxmd.com/read/29323051/notch-pathway-inhibitor-dapt-enhances-atoh1-activity-to-generate-new-hair-cells-in-situ-in-rat-cochleae
#5
Wen-Wei Luo, Zhao Han, Dong-Dong Ren, Xin-Wei Wang, Fang-Lu Chi, Juan-Mei Yang
Atoh1 overexpression in cochlear epithelium induces new hair cell formation. Use of adenovirus-mediated Atoh1 overexpression has mainly focused on the rat lesser epithelial ridge and induces ectopic hair cell regeneration. The sensory region of rat cochlea is difficult to transfect, thus new hair cells are rarely produced in situ in rat cochlear explants. After culturing rat cochleae in medium containing 10% fetal bovine serum, adenovirus successfully infected the sensory region as the width of the supporting cell area was significantly increased...
December 2017: Neural Regeneration Research
https://www.readbyqxmd.com/read/29321651/auditory-neural-activity-in-congenitally-deaf-mice-induced-by-infrared-neural-stimulation
#6
Xiaodong Tan, Israt Jahan, Yingyue Xu, Stuart Stock, Changyow Claire Kwan, Carmen Soriano, Xianghui Xiao, Jaime García-Añoveros, Bernd Fritzsch, Claus-Peter Richter
To determine whether responses during infrared neural stimulation (INS) result from the direct interaction with spiral ganglion neurons (SGNs), we tested three genetically modified deaf mouse models: Atoh1-cre; Atoh1 f/f (Atoh1 conditional knockout, CKO), Atoh1-cre; Atoh1 f/kiNeurog1 (Neurog1 knockin, KI), and the Vglut3 knockout (Vglut3 -/- ) mice. All animals were exposed to tone bursts and clicks up to 107 dB (re 20 µPa) and to INS, delivered with a 200 µm optical fiber. The wavelength (λ) was 1860 nm, the radiant energy (Q) 0-800 µJ/pulse, and the pulse width (PW) 100-500 µs...
January 10, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29317485/meis1-coordinates-cerebellar-granule-cell-development-by-regulating-pax6-transcription-bmp-signaling-and-atoh1-degradation
#7
Tomoo Owa, Shinichiro Taya, Satoshi Miyashita, Mariko Yamashita, Toma Adachi, Koyo Yamada, Miwa Yokoyama, Shogo Aida, Tomoki Nishioka, Yukiko U Inoue, Ryo Goitsuka, Takuro Nakamura, Takayoshi Inoue, Kozo Kaibuchi, Mikio Hoshino
Cerebellar granule cell precursors (GCPs) and granule cells (GCs) represent good models to study neuronal development. Here, we report that the transcription factor myeloid ectopic viral integration site 1 homolog (Meis1) plays pivotal roles in the regulation of mouse GC development. We found that Meis1 is expressed in GC lineage cells and astrocytes in the cerebellum during development. Targeted disruption of the Meis1 gene specifically in the GC lineage resulted in smaller cerebella with disorganized lobules...
January 31, 2018: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/29241683/notch-pathway-signaling-in-the-skin-antagonizes-merkel-cell-development
#8
Gregory J Logan, Margaret C Wright, Adam C Kubicki, Stephen M Maricich
Merkel cells are mechanosensitive skin cells derived from the epidermal lineage whose development requires expression of the basic helix-loop-helix transcription factor Atoh1. The genes and pathways involved in regulating Merkel cell development during embryogenesis are poorly understood. Notch pathway signaling antagonizes Atoh1 expression in many developing body regions, so we hypothesized that Notch signaling might inhibit Merkel cell development. We found that conditional, constitutive overexpression of the Notch intracellular domain (NICD) in mouse epidermis significantly decreased Merkel cell numbers in whisker follicles and touch domes of hairy skin...
February 15, 2018: Developmental Biology
https://www.readbyqxmd.com/read/29233556/contribution-of-atoh1-cells-to-the-homeostasis-repair-and-tumorigenesis-of-the-colonic-epithelium
#9
Fumiaki Ishibashi, Hiromichi Shimizu, Toru Nakata, Satoru Fujii, Kohei Suzuki, Ami Kawamoto, Sho Anzai, Reiko Kuno, Sayaka Nagata, Go Ito, Tatsuro Murano, Tomohiro Mizutani, Shigeru Oshima, Kiichiro Tsuchiya, Tetsuya Nakamura, Mamoru Watanabe, Ryuichi Okamoto
ATOH1 is a master transcription factor for the secretory lineage differentiation of intestinal epithelial cells (IECs). However, the comprehensive contribution of ATOH1+ secretory lineage IECs to the homeostasis, repair, and tumorigenesis of the intestinal epithelium remains uncertain. Through our ATOH1+ cell-lineage tracing, we show here that a definite number of ATOH1+ IECs retain stem cell properties and can form ATOH1+ IEC-derived clonal ribbons (ATOH1+ ICRs) under completely homeostatic conditions. Interestingly, colonic ATOH1+ IECs appeared to exhibit their stem cell function more frequently compared with those of the small intestine...
January 9, 2018: Stem Cell Reports
https://www.readbyqxmd.com/read/29168692/jak2-mediated-phosphorylation-of-atoh1-is-critical-for-medulloblastoma-growth
#10
Tiemo J Klisch, Anna Vainshtein, Akash J Patel, Huda Y Zoghbi
Treatment for medulloblastoma, the most common malignant brain tumor in children, remains limited to surgical resection, radiation, and traditional chemotherapy; with long-term survival as low as 50-60% for Sonic Hedgehog (Shh)-type medulloblastoma. We have shown that the transcription factor Atonal homologue 1 (Atoh1) is required for Shh-type medulloblastoma development in mice. To determine whether reducing either Atoh1 levels or activity in tumors after their development is beneficial, we studied Atoh1 dosage and modifications in Shh-type medulloblastoma...
November 23, 2017: ELife
https://www.readbyqxmd.com/read/29153838/unsupervised-trajectory-analysis-of-single-cell-rna-seq-and-imaging-data-reveals-alternative-tuft-cell-origins-in-the-gut
#11
Charles A Herring, Amrita Banerjee, Eliot T McKinley, Alan J Simmons, Jie Ping, Joseph T Roland, Jeffrey L Franklin, Qi Liu, Michael J Gerdes, Robert J Coffey, Ken S Lau
Modern single-cell technologies allow multiplexed sampling of cellular states within a tissue. However, computational tools that can infer developmental cell-state transitions reproducibly from such single-cell data are lacking. Here, we introduce p-Creode, an unsupervised algorithm that produces multi-branching graphs from single-cell data, compares graphs with differing topologies, and infers a statistically robust hierarchy of cell-state transitions that define developmental trajectories. We have applied p-Creode to mass cytometry, multiplex immunofluorescence, and single-cell RNA-seq data...
January 24, 2018: Cell Systems
https://www.readbyqxmd.com/read/29104531/the-repression-of-atoh1-by-neurogenin1-during-inner-ear-development
#12
Héctor Gálvez, Juan J Tena, Fernando Giraldez, Gina Abelló
Atonal homolog 1 (Atoh1) and Neurogenin1 (Neurog1) are basic Helix-Loop-Helix (bHLH) transcription factors crucial for the generation of hair cells (HCs) and neurons in the inner ear. Both genes are induced early in development, but the expression of Atoh1 is counteracted by Neurog1. As a result, HC development is prevented during neurogenesis. This work aimed at understanding the molecular basis of this interaction. Atoh1 regulation depends on a 3'Atoh1-enhancer that is the site for Atoh1 autoregulation. Reporter assays on chick embryos and P19 cells show that Neurog1 hampers the autoactivation of Atoh1, the effect being cell autonomous and independent on Notch activity...
2017: Frontiers in Molecular Neuroscience
https://www.readbyqxmd.com/read/29084289/neuronal-differentiation-of-hair-follicle-bulge-derived-stem-cells-co-cultured-with-mouse-cochlear-modiolus-explants
#13
Timo Schomann, Laura Mezzanotte, John C M J De Groot, Marcelo N Rivolta, Sanne H Hendriks, Johan H M Frijns, Margriet A Huisman
Stem-cell-based repair of auditory neurons may represent an attractive therapeutic option to restore sensorineural hearing loss. Hair-follicle-bulge-derived stem cells (HFBSCs) are promising candidates for this type of therapy, because they (1) have migratory properties, enabling migration after transplantation, (2) can differentiate into sensory neurons and glial cells, and (3) can easily be harvested in relatively high numbers. However, HFBSCs have never been used for this purpose. We hypothesized that HFBSCs can be used for cell-based repair of the auditory nerve and we have examined their migration and incorporation into cochlear modiolus explants and their subsequent differentiation...
2017: PloS One
https://www.readbyqxmd.com/read/29044151/modeling-and-preventing-progressive-hearing-loss-in-usher-syndrome-iii
#14
Ruishuang Geng, Akil Omar, Suhasini R Gopal, Daniel H-C Chen, Ruben Stepanyan, Martin L Basch, Astra Dinculescu, David N Furness, David Saperstein, William Hauswirth, Lawrence R Lustig, Kumar N Alagramam
Usher syndrome type III (USH3) characterized by progressive loss of vision and hearing is caused by mutations in the clarin-1 gene (CLRN1). Clrn1 knockout (KO) mice develop hair cell defects by postnatal day 2 (P2) and are deaf by P21-P25. Early onset profound hearing loss in KO mice and lack of information about the cochlear cell type that requires Clrn1 expression pose challenges to therapeutic investigation. We generated KO mice harboring a transgene, TgAC1, consisting of Clrn1-UTR (Clrn1 cDNA including its 5' and 3' UTR) under the control of regulatory elements (Atoh1 3' enhancer/β-globin basal promoter) to direct expression of Clrn1 in hair cells during development and down regulate it postnatally...
October 18, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28899994/heterodimeric-capping-protein-is-required-for-stereocilia-length-and-width-regulation
#15
Matthew R Avenarius, Jocelyn F Krey, Rachel A Dumont, Clive P Morgan, Connor B Benson, Sarath Vijayakumar, Christopher L Cunningham, Deborah I Scheffer, David P Corey, Ulrich Müller, Sherri M Jones, Peter G Barr-Gillespie
Control of the dimensions of actin-rich processes like filopodia, lamellipodia, microvilli, and stereocilia requires the coordinated activity of many proteins. Each of these actin structures relies on heterodimeric capping protein (CAPZ), which blocks actin polymerization at barbed ends. Because dimension control of the inner ear's stereocilia is particularly precise, we studied the CAPZB subunit in hair cells. CAPZB, present at ∼100 copies per stereocilium, concentrated at stereocilia tips as hair cell development progressed, similar to the CAPZB-interacting protein TWF2...
November 6, 2017: Journal of Cell Biology
https://www.readbyqxmd.com/read/28892484/six1-is-essential-for-differentiation-and-patterning-of-the-mammalian-auditory-sensory-epithelium
#16
Ting Zhang, Jinshu Xu, Pascal Maire, Pin-Xian Xu
The organ of Corti in the cochlea is a two-cell layered epithelium: one cell layer of mechanosensory hair cells that align into one row of inner and three rows of outer hair cells interdigitated with one cell layer of underlying supporting cells along the entire length of the cochlear spiral. These two types of epithelial cells are derived from common precursors in the four- to five-cell layered primordium and acquire functionally important shapes during terminal differentiation through the thinning process and convergent extension...
September 2017: PLoS Genetics
https://www.readbyqxmd.com/read/28751305/dlx3b-4b-is-required-for-early-born-but-not-later-forming-sensory-hair-cells-during-zebrafish-inner-ear-development
#17
Simone Schwarzer, Sandra Spieß, Michael Brand, Stefan Hans
Morpholino-mediated knockdown has shown that the homeodomain transcription factors Dlx3b and Dlx4b are essential for proper induction of the otic-epibranchial progenitor domain (OEPD), as well as subsequent formation of sensory hair cells in the developing zebrafish inner ear. However, increasing use of reverse genetic approaches has revealed poor correlation between morpholino-induced and mutant phenotypes. Using CRISPR/Cas9-mediated mutagenesis, we generated a defined deletion eliminating the entire open reading frames of dlx3b and dlx4b (dlx3b/4b) and investigated a potential phenotypic difference between mutants and morpholino-mediated knockdown...
September 15, 2017: Biology Open
https://www.readbyqxmd.com/read/28729444/an-atoh1-s193a-phospho-mutant-allele-causes-hearing-deficits-and-motor-impairment
#18
Wei Rose Xie, Hsin-I Jen, Michelle L Seymour, Szu-Ying Yeh, Fred A Pereira, Andrew K Groves, Tiemo J Klisch, Huda Y Zoghbi
Atonal homolog 1 (Atoh1) is a basic helix-loop-helix (bHLH) transcription factor that is essential for the genesis, survival, and maturation of a variety of neuronal and non-neuronal cell populations, including those involved in proprioception, interoception, balance, respiration, and hearing. Such diverse functions require fine regulation at the transcriptional and protein levels. Here, we show that serine 193 (S193) is phosphorylated in Atoh1's bHLH domain in vivo Knock-in mice of both sexes bearing a GFP-tagged phospho-dead S193A allele on a null background ( Atoh1 S193A/lacZ ) exhibit mild cerebellar foliation defects, motor impairments, partial pontine nucleus migration defects, cochlear hair cell degeneration, and profound hearing loss...
September 6, 2017: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/28686713/transcriptome-wide-comparison-of-the-impact-of-atoh1-and-mir-183-family-on-pluripotent-stem-cells-and-multipotent-otic-progenitor-cells
#19
COMPARATIVE STUDY
Michael Ebeid, Prashanth Sripal, Jason Pecka, Kirk W Beisel, Kelvin Kwan, Garrett A Soukup
Over 5% of the global population suffers from disabling hearing loss caused by multiple factors including aging, noise exposure, genetic predisposition, or use of ototoxic drugs. Sensorineural hearing loss is often caused by the loss of sensory hair cells (HCs) of the inner ear. A barrier to hearing restoration after HC loss is the limited ability of mammalian auditory HCs to spontaneously regenerate. Understanding the molecular mechanisms orchestrating HC development is expected to facilitate cell replacement therapies...
2017: PloS One
https://www.readbyqxmd.com/read/28646272/rhesus-cochlear-and-vestibular-functions-are-preserved-after-inner-ear-injection-of-saline-volume-sufficient-for-gene-therapy-delivery
#20
Chenkai Dai, Mohamed Lehar, Daniel Q Sun, Lani Swarthout Rvt, John P Carey, Tim MacLachlan, Doug Brough, Hinrich Staecker, Alexandra M Della Santina, Timothy E Hullar, Charles C Della Santina
Sensorineural losses of hearing and vestibular sensation due to hair cell dysfunction are among the most common disabilities. Recent preclinical research demonstrates that treatment of the inner ear with a variety of compounds, including gene therapy agents, may elicit regeneration and/or repair of hair cells in animals exposed to ototoxic medications or other insults to the inner ear. Delivery of gene therapy may also offer a means for treatment of hereditary hearing loss. However, injection of a fluid volume sufficient to deliver an adequate dose of a pharmacologic agent could, in theory, cause inner ear trauma that compromises functional outcome...
August 2017: Journal of the Association for Research in Otolaryngology: JARO
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