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Article: Early-Onset Hearing Loss in Mouse Models of Alzheimer's Disease and Increased DNA Damage in the Cochlea.

Park, Jae-Hyeon / Sahbaz, Burcin Duan / Pekhale, Komal / Chu, Xixia / Okur, Mustafa N / Grati, Mhamed / Isgrig, Kevin / Chien, Wade / Chrysostomou, Elena / Sullivan, Lauren / Croteau, Deborah L / Manor, Uri / Bohr, Vilhelm A

Aging Biology

2024 Volume 1

Abstract: There is considerable interest in whether sensory deficiency is associated with the development of Alzheimer's disease (AD). Notably, the relationship between hearing impairment and AD is of high relevance but still poorly understood. In this study, we ... ...

Abstract	There is considerable interest in whether sensory deficiency is associated with the development of Alzheimer's disease (AD). Notably, the relationship between hearing impairment and AD is of high relevance but still poorly understood. In this study, we found early-onset hearing loss in two AD mouse models, 3xTgAD and 3xTgAD/Polβ
Language	English
Publishing date	2024-02-20
Publishing country	United States
Document type	Journal Article
DOI	10.59368/agingbio.20240025
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Article ; Online: The Notch Ligand Jagged1 Is Required for the Formation, Maintenance, and Survival of Hensen's Cells in the Mouse Cochlea.

Chrysostomou, Elena / Zhou, Luyi / Darcy, Yuanzhao L / Graves, Kaley A / Doetzlhofer, Angelika / Cox, Brandon C

The Journal of neuroscience : the official journal of the Society for Neuroscience

2020 Volume 40, Issue 49, Page(s) 9401–9413

Abstract: During cochlear development, the Notch ligand JAGGED 1 (JAG1) plays an important role in the specification of the prosensory region, which gives rise to sound-sensing hair cells and neighboring supporting cells (SCs). While JAG1's expression is ... ...

Abstract	During cochlear development, the Notch ligand JAGGED 1 (JAG1) plays an important role in the specification of the prosensory region, which gives rise to sound-sensing hair cells and neighboring supporting cells (SCs). While JAG1's expression is maintained in SCs through adulthood, the function of JAG1 in SC development is unknown. Here, we demonstrate that JAG1 is essential for the formation and maintenance of Hensen's cells, a highly specialized SC subtype located at the edge of the auditory epithelium. Using
MeSH term(s)	Animals ; Cell Survival ; Cochlea/cytology ; Cochlea/growth & development ; Cochlea/metabolism ; Down-Regulation ; Evoked Potentials, Auditory, Brain Stem ; Female ; Gene Expression Regulation, Developmental ; Immunohistochemistry ; Jagged-1 Protein/genetics ; Jagged-1 Protein/metabolism ; Labyrinth Supporting Cells/physiology ; Male ; Mice ; Mice, Knockout ; Pregnancy ; SOXB1 Transcription Factors/genetics ; SOXB1 Transcription Factors/metabolism
Chemical Substances	Jag1 protein, mouse ; Jagged-1 Protein ; SOXB1 Transcription Factors ; Sox2 protein, mouse
Language	English
Publishing date	2020-10-30
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	604637-x
ISSN	1529-2401 ; 0270-6474
ISSN (online)	1529-2401
ISSN	0270-6474
DOI	10.1523/JNEUROSCI.1192-20.2020
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Article ; Online: Canonical Notch signaling plays an instructive role in auditory supporting cell development.

Campbell, Dean P / Chrysostomou, Elena / Doetzlhofer, Angelika

Scientific reports

2016 Volume 6, Page(s) 19484

Abstract: The auditory sensory epithelium, composed of mechano-sensory hair cells (HCs) and highly specialized glial-like supporting cells (SCs), is critical for our ability to detect sound. SCs provide structural and functional support to HCs and play an ... ...

Abstract	The auditory sensory epithelium, composed of mechano-sensory hair cells (HCs) and highly specialized glial-like supporting cells (SCs), is critical for our ability to detect sound. SCs provide structural and functional support to HCs and play an essential role in cochlear development, homeostasis and repair. Despite their importance, however, surprisingly little is known about the molecular mechanisms guiding SC differentiation. Here, we provide evidence that in addition to its well-characterized inhibitory function, canonical Notch signaling plays a positive, instructive role in the differentiation of SCs. Using γ-secretase inhibitor DAPT to acutely block canonical Notch signaling, we identified a cohort of Notch-regulated SC-specific genes, with diverse functions in cell signaling, cell differentiation, neuronal innervation and synaptogenesis. We validated the newly identified Notch-regulated genes in vivo using genetic gain (Emx2(Cre/+); Rosa26(N1ICD/+)) and loss-of-function approaches (Emx2(Cre/+); Rosa26(DnMAML1/+)). Furthermore, we demonstrate that Notch over-activation in the differentiating murine cochlea (Emx2(Cre/+); Rosa26(N1ICD/+)) actively promotes a SC-specific gene expression program. Finally, we show that outer SCs -so called Deiters' cells are selectively lost by prolonged reduction (Emx2(Cre/+); Rosa26(DnMAML1/+/+)) or abolishment of canonical Notch signaling (Fgfr3-iCreER; Rbpj(-/Δ)), indicating a critical role for Notch signaling in Deiters' cell development.
MeSH term(s)	Animals ; Cell Count ; Cell Death ; Cell Differentiation/genetics ; Cochlea/cytology ; Cochlea/embryology ; Cochlea/metabolism ; Gene Expression Profiling ; Gene Expression Regulation, Developmental ; Labyrinth Supporting Cells/cytology ; Labyrinth Supporting Cells/metabolism ; Mice ; Mice, Transgenic ; Nuclear Proteins/genetics ; Nuclear Proteins/metabolism ; Organ Specificity/genetics ; Phenotype ; Receptors, Notch/metabolism ; Signal Transduction ; Transcription Factors/genetics ; Transcription Factors/metabolism
Chemical Substances	Maml1 protein, mouse ; Nuclear Proteins ; Receptors, Notch ; Transcription Factors
Language	English
Publishing date	2016-01-20
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/srep19484
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Article ; Online: Delta-like 1 and lateral inhibition during hair cell formation in the chicken inner ear: evidence against cis-inhibition.

Chrysostomou, Elena / Gale, Jonathan E / Daudet, Nicolas

Development (Cambridge, England)

2012 Volume 139, Issue 20, Page(s) 3764–3774

Abstract: The formation of the salt-and-pepper mosaic of hair cells and supporting cells in the sensory epithelia of the inner ear is regulated by Notch signalling and lateral inhibition, but the dynamics of this process and precise mode of action of delta-like 1 ( ...

Abstract	The formation of the salt-and-pepper mosaic of hair cells and supporting cells in the sensory epithelia of the inner ear is regulated by Notch signalling and lateral inhibition, but the dynamics of this process and precise mode of action of delta-like 1 (Dll1) in this context are unclear. Here, we transfected the chicken inner ear with a fluorescent reporter that includes elements of the mammalian Hes5 promoter to monitor Notch activity in the developing sensory patches. The Hes5 reporter was active in proliferating cells and supporting cells, and Dll1 expression was highest in prospective hair cells with low levels of Notch activity, which occasionally contacted more differentiated hair cells. To investigate Dll1 functions we used constructs in which Dll1 expression was either constitutive, regulated by the Hes5 promoter, or induced by doxycycline. In support of the standard lateral inhibition model, both continuous and Hes5-regulated expression of Dll1 promoted hair cell differentiation cell-autonomously (in cis) and inhibited hair cell formation in trans. However, some hair cells formed despite contacting Dll1-overexpressing cells, suggesting that some progenitor cells are insensitive to lateral inhibition. This is not due to the cis-inhibition of Notch activity by Dll1 itself, as induction of Dll1 did not cell-autonomously reduce the activity of the Hes5 reporter in progenitor and supporting cells. Altogether, our results show that Dll1 functions primarily in trans to regulate hair cell production but also that additional mechanisms operate downstream of lateral inhibition to eliminate patterning errors in the sensory epithelia of the inner ear.
MeSH term(s)	Animals ; Cell Differentiation ; Cell Proliferation ; Chick Embryo ; Doxycycline/pharmacology ; Ear, Inner/embryology ; Ear, Inner/metabolism ; Gene Expression Regulation, Developmental ; Genes, Reporter ; Hair Cells, Auditory, Inner/cytology ; Hair Cells, Auditory, Inner/metabolism ; Intracellular Signaling Peptides and Proteins/metabolism ; Membrane Proteins/metabolism ; Receptors, Notch/metabolism ; Signal Transduction
Chemical Substances	Intracellular Signaling Peptides and Proteins ; Membrane Proteins ; Receptors, Notch ; delta protein ; Doxycycline (N12000U13O)
Language	English
Publishing date	2012-09-18
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	90607-4
ISSN	1477-9129 ; 0950-1991
ISSN (online)	1477-9129
ISSN	0950-1991
DOI	10.1242/dev.074476
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Article ; Online: Shaping of inner ear sensory organs through antagonistic interactions between Notch signalling and Lmx1a.

Mann, Zoe F / Gálvez, Héctor / Pedreno, David / Chen, Ziqi / Chrysostomou, Elena / Żak, Magdalena / Kang, Miso / Canden, Elachumee / Daudet, Nicolas

eLife

2017 Volume 6

Abstract: The mechanisms of formation of the distinct sensory organs of the inner ear and the non-sensory domains that separate them are still unclear. Here, we show that several sensory patches arise by progressive segregation from a common prosensory domain in ... ...

Abstract	The mechanisms of formation of the distinct sensory organs of the inner ear and the non-sensory domains that separate them are still unclear. Here, we show that several sensory patches arise by progressive segregation from a common prosensory domain in the embryonic chicken and mouse otocyst. This process is regulated by mutually antagonistic signals: Notch signalling and Lmx1a. Notch-mediated lateral induction promotes prosensory fate. Some of the early Notch-active cells, however, are normally diverted from this fate and increasing lateral induction produces misshapen or fused sensory organs in the chick. Conversely Lmx1a (or cLmx1b in the chick) allows sensory organ segregation by antagonizing lateral induction and promoting commitment to the non-sensory fate. Our findings highlight the dynamic nature of sensory patch formation and the labile character of the sensory-competent progenitors, which could have facilitated the emergence of new inner ear organs and their functional diversification in the course of evolution.
MeSH term(s)	Animals ; Chickens ; Ear, Inner/anatomy & histology ; Ear, Inner/embryology ; Ear, Inner/metabolism ; Gene Expression Regulation, Developmental ; Jagged-1 Protein/genetics ; Jagged-1 Protein/metabolism ; LIM-Homeodomain Proteins/metabolism ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Organogenesis ; Receptors, Notch/genetics ; Receptors, Notch/metabolism ; Signal Transduction
Chemical Substances	Jag1 protein, mouse ; Jagged-1 Protein ; LIM-Homeodomain Proteins ; Receptors, Notch
Language	English
Publishing date	2017-12-04
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2687154-3
ISSN	2050-084X ; 2050-084X
ISSN (online)	2050-084X
ISSN	2050-084X
DOI	10.7554/eLife.33323
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Article ; Online: Tol2-mediated gene transfer and in ovo electroporation of the otic placode: a powerful and versatile approach for investigating embryonic development and regeneration of the chicken inner ear.

Freeman, Stephen / Chrysostomou, Elena / Kawakami, Koichi / Takahashi, Yoshiko / Daudet, Nicolas

Methods in molecular biology (Clifton, N.J.)

2012 Volume 916, Page(s) 127–139

Abstract: The vertebrate inner ear is composed of several specialized epithelia containing mechanosensory "hair" cells, sensitive to sound and head movements. In mammals, the loss of hair cells for example during aging or after noise trauma is irreversible and ... ...

Abstract	The vertebrate inner ear is composed of several specialized epithelia containing mechanosensory "hair" cells, sensitive to sound and head movements. In mammals, the loss of hair cells for example during aging or after noise trauma is irreversible and results in permanent sensory deficits. By contrast, avian, fish, and amphibians can efficiently regenerate lost hair cells following trauma. The chicken inner ear is a classic model system to investigate the cellular and molecular mechanisms of inner ear development and regeneration, yet it suffered until recently from a relative lack of flexible tools for genetic studies. With the introduction of in ovo electroporation and of Tol2 transposon vectors for gene transfer in avian cells, the field of experimental possibilities has now expanded significantly in this model. Here we provide a general protocol for in ovo electroporation of the chicken otic placode and illustrate how this approach, combined with Tol2 vectors, can be used to drive long-term and inducible gene expression in the embryonic chicken inner ear. This method will be particularly useful to investigate the function of candidate genes regulating progenitor cell behavior and sensory cell differentiation in the inner ear.
MeSH term(s)	Animals ; Chickens ; DNA Transposable Elements/genetics ; Ear, Inner/cytology ; Ear, Inner/embryology ; Ear, Inner/metabolism ; Ear, Inner/physiology ; Ectoderm/embryology ; Ectoderm/metabolism ; Electroporation/methods ; Genetic Vectors/genetics ; Regeneration/genetics ; Transfection/instrumentation ; Transfection/methods
Chemical Substances	DNA Transposable Elements
Language	English
Publishing date	2012-08-23
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	1940-6029
ISSN (online)	1940-6029
DOI	10.1007/978-1-61779-980-8_10
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Article ; Online: gEAR: Gene Expression Analysis Resource portal for community-driven, multi-omic data exploration.

Nature methods

2021 Volume 18, Issue 8, Page(s) 843–844

MeSH term(s)	Algorithms ; Brain/metabolism ; Computational Biology/methods ; Computer Graphics ; Gene Expression Regulation ; Genomics/methods ; Humans ; Software ; Transcriptome
Language	English
Publishing date	2021-06-11
Publishing country	United States
Document type	Letter ; Research Support, N.I.H., Extramural
ZDB-ID	2169522-2
ISSN	1548-7105 ; 1548-7091
ISSN (online)	1548-7105
ISSN	1548-7091
DOI	10.1038/s41592-021-01200-9
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Article ; Online: The Neuroscience Multi-Omic Archive: a BRAIN Initiative resource for single-cell transcriptomic and epigenomic data from the mammalian brain.

Ament, Seth A / Adkins, Ricky S / Carter, Robert / Chrysostomou, Elena / Colantuoni, Carlo / Crabtree, Jonathan / Creasy, Heather H / Degatano, Kylee / Felix, Victor / Gandt, Peter / Garden, Gwenn A / Giglio, Michelle / Herb, Brian R / Khajouei, Farzaneh / Kiernan, Elizabeth / McCracken, Carrie / McDaniel, Kennedy / Nadendla, Suvarna / Nickel, Lance /

Olley, Dustin / Orvis, Joshua / Receveur, Joseph P / Schor, Mike / Sonthalia, Shreyash / Tickle, Timothy L / Way, Jessica / Hertzano, Ronna / Mahurkar, Anup A / White, Owen R

Nucleic acids research

2022 Volume 51, Issue D1, Page(s) D1075–D1085

Abstract: Scalable technologies to sequence the transcriptomes and epigenomes of single cells are transforming our understanding of cell types and cell states. The Brain Research through Advancing Innovative Neurotechnologies (BRAIN) Initiative Cell Census Network ...

Abstract	Scalable technologies to sequence the transcriptomes and epigenomes of single cells are transforming our understanding of cell types and cell states. The Brain Research through Advancing Innovative Neurotechnologies (BRAIN) Initiative Cell Census Network (BICCN) is applying these technologies at unprecedented scale to map the cell types in the mammalian brain. In an effort to increase data FAIRness (Findable, Accessible, Interoperable, Reusable), the NIH has established repositories to make data generated by the BICCN and related BRAIN Initiative projects accessible to the broader research community. Here, we describe the Neuroscience Multi-Omic Archive (NeMO Archive; nemoarchive.org), which serves as the primary repository for genomics data from the BRAIN Initiative. Working closely with other BRAIN Initiative researchers, we have organized these data into a continually expanding, curated repository, which contains transcriptomic and epigenomic data from over 50 million brain cells, including single-cell genomic data from all of the major regions of the adult and prenatal human and mouse brains, as well as substantial single-cell genomic data from non-human primates. We make available several tools for accessing these data, including a searchable web portal, a cloud-computing interface for large-scale data processing (implemented on Terra, terra.bio), and a visualization and analysis platform, NeMO Analytics (nemoanalytics.org).
MeSH term(s)	Animals ; Mice ; Epigenomics ; Genomics ; Mammals ; Multiomics ; Primates ; Transcriptome ; Brain/cytology ; Brain/metabolism ; Databases, Genetic
Language	English
Publishing date	2022-10-31
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	186809-3
ISSN	1362-4962 ; 1362-4954 ; 0301-5610 ; 0305-1048
ISSN (online)	1362-4962 ; 1362-4954
ISSN	0301-5610 ; 0305-1048
DOI	10.1093/nar/gkac962
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