scholarly journals Let-7 miRNAs control auditory sensory progenitor behavior in the vertebrate inner ear

2019 ◽  
Author(s):  
Lale Evsen ◽  
Shuran Zhang ◽  
Angelika Doetzlhofer
Keyword(s):  
Protein Expression ◽  
Inner Ear ◽  
Sensory Cell ◽  
Basilar Papilla ◽  
State Transitions ◽  
Sensory Cells ◽  
Chromatin Remodeler ◽  
Self Renewal ◽  
Auditory Organ

ABSTRACTThe evolutionary conserved lethal-7 (let-7) family of microRNAs (miRNAs) is a well-known activator of terminal mitosis and differentiation. Surprisingly, we previously found that overexpression of let-7 miRNAs in the murine auditory organ accelerated the terminal mitosis of auditory sensory progenitors (pro-sensory cells) but failed to stimulate their differentiation into mechano-sensory hair cells (HCs). To further address the role of let-7 miRNAs in auditory sensory differentiation, we conducted gain and loss of function experiments in the developing chicken auditory organ, the basilar papilla (BP). Using a sponge approach, we show that the disruption of let-7 miRNA function in the developing BP delays pro-sensory cell exit and delays differentiation of auditory HCs, revealing that endogenous let-7 miRNAs limit pro-sensory cell self-renewal in the developing BP. However, consistent with the role of let-7 miRNAs in the murine auditory organ, let-7b overexpression in the developing BP delayed HC differentiation, suggesting that too low or too high let-7 miRNA levels disrupt HC differentiation. Furthermore, we provide evidence that the repressive role of let-7 miRNAs in HC differentiation may be due to its targeting of the chromatin remodeler CHD7. Mutation in the human CHD7 gene causes CHARGE syndrome, which amongst others is characterized by inner ear and hearing deficits. Using target prediction algorithms, we uncovered a highly predictive and evolutionary conserved let-7 binding site within the Chd7 transcript. Consistent with being a target of let-7 repression, we demonstrate that let-7b overexpression significantly reduced CHD7 protein expression in to the developing BP. Furthermore, utilizing an inducible let-7g transgenic mouse model, we show that let-7 miRNAs negatively regulate CHD7 protein expression in developing murine cochlear, retinal and brain tissue. CHD7 is dosage dependent and the here described regulation by let-7 miRNAs may be critical to fine tune CHD7 protein levels during sensory and neuronal development.SIGNIFICANCEThe evolutionary highly conserved let-7 miRNAs are essential for proper timing of cell state transitions during embryogenesis. Even though abundantly expressed in the vertebrate auditory organ, surprisingly little is known about their function in auditory sensory differentiation. Here, we demonstrate that endogenous let-7 miRNAs are essential for limiting auditory sensory progenitor (pro-sensory) cell self-renewal. Furthermore, we find that precocious let-7 miRNAs expression interferes with auditory hair cell differentiation and identify chromatin remodeler CHD7 as a potential target gene of let-7 repressive function in HC differentiation.

scholarly journals let-7 miRNAs inhibit CHD7 expression and control auditory-sensory progenitor cell behavior in the developing inner ear

Development ◽  
2020 ◽  
Vol 147 (15) ◽  
pp. dev183384
Author(s):  
Lale Evsen ◽  
Xiaojun Li ◽  
Shuran Zhang ◽  
Sharjil Razin ◽  
Angelika Doetzlhofer
Keyword(s):  
Inner Ear ◽  
Hair Cells ◽  
Progenitor Cell ◽  
Charge Syndrome ◽  
Basilar Papilla ◽  
Sensory Hair Cells ◽  
Evolutionarily Conserved ◽  
Auditory Organ ◽  
And Control

ABSTRACTThe evolutionarily conserved lethal-7 (let-7) microRNAs (miRNAs) are well-known activators of proliferative quiescence and terminal differentiation. However, in the murine auditory organ, let-7g overexpression delays the differentiation of mechano-sensory hair cells (HCs). To address whether the role of let-7 in auditory-sensory differentiation is conserved among vertebrates, we manipulated let-7 levels within the chicken auditory organ: the basilar papilla. Using a let-7 sponge construct to sequester let-7 miRNAs, we found that endogenous let-7 miRNAs are essential for limiting the self-renewal of HC progenitor cells. Furthermore, let-7b overexpression experiments revealed that, similar to mice, higher than normal let-7 levels slow/delay HC differentiation. Finally, we identify CHD7, a chromatin remodeler, as a candidate for mediating the repressive function of let-7 in HC differentiation and inner ear morphogenesis. Our analysis uncovered an evolutionarily conserved let-7-5p-binding site within the chicken Chd7 gene and its human and murine homologs, and we show that let-7g overexpression in mice limits CHD7 expression in the developing inner ear, retina and brain. Haploinsufficiency of CHD7 in humans causes CHARGE syndrome and attenuation of let-7 function may be an effective method for treating CHD7 deficiency.

scholarly journals Innate Immunity to Spiral Ganglion Neuron Loss: A Neuroprotective Role of Fractalkine Signaling in Injured Cochlea

2021 ◽  
Vol 15 ◽  
Author(s):  
Andrew Rigel Stothert ◽  
Tejbeer Kaur
Keyword(s):  
Innate Immunity ◽  
Nervous System ◽  
Immune System ◽  
Inner Ear ◽  
Immune Cells ◽  
Spiral Ganglion ◽  
Sensory Cells ◽  
Specific Chemical ◽  
Ganglion Neurons

Immune system dysregulation is increasingly being attributed to the development of a multitude of neurodegenerative diseases. This, in large part, is due to the delicate relationship that exists between neurons in the central nervous system (CNS) and peripheral nervous system (PNS), and the resident immune cells that aid in homeostasis and immune surveillance within a tissue. Classically, the inner ear was thought to be immune privileged due to the presence of a blood-labyrinth barrier. However, it is now well-established that both vestibular and auditory end organs in the inner ear contain a resident (local) population of macrophages which are the phagocytic cells of the innate-immune system. Upon cochlear sterile injury or infection, there is robust activation of these resident macrophages and a predominant increase in the numbers of macrophages as well as other types of leukocytes. Despite this, the source, nature, fate, and functions of these immune cells during cochlear physiology and pathology remains unclear. Migration of local macrophages and infiltration of bone-marrow-derived peripheral blood macrophages into the damaged cochlea occur through various signaling cascades, mediated by the release of specific chemical signals from damaged sensory and non-sensory cells of the cochlea. One such signaling pathway is CX3CL1-CX3CR1, or fractalkine (FKN) signaling, a direct line of communication between macrophages and sensory inner hair cells (IHCs) and spiral ganglion neurons (SGNs) of the cochlea. Despite the known importance of this neuron-immune axis in CNS function and pathology, until recently it was not clear whether this signaling axis played a role in macrophage chemotaxis and SGN survival following cochlear injury. In this review, we will explore the importance of innate immunity in neurodegenerative disease development, specifically focusing on the regulation of the CX3CL1-CX3CR1 axis, and present evidence for a role of FKN signaling in cochlear neuroprotection.

EYA1 Expression in the Developing Inner Ear

2005 ◽  
Vol 114 (11) ◽  
pp. 853-858 ◽  
Author(s):  
Brian C. Bane ◽  
Jana M. Van Rybroek ◽  
Sandra J. Kolker ◽  
Daniel L. Weeks ◽  
Jose M. Manaligod
Keyword(s):  
Cell Differentiation ◽  
Xenopus Laevis ◽  
Inner Ear ◽  
Sensory Cell ◽  
Confocal Imaging ◽  
Sensory Cells ◽  
Protein Distribution ◽  
Developmental Anatomy ◽  
Anterior Aspect ◽  
Endolymphatic Duct

Objectives: We sought to determine the developmental anatomy and EYA1 protein distribution in the inner ear of Xenopus laevis. Methods: Xenopus laevis embryos were stained with monoclonal antibodies and imaged with confocal microscopy. Results: At stage 27, the otocyst fully forms, with strong tubulin staining of early sensory cells at its ventromedial aspect. Neuronal ingrowth follows at stage 33/34. At stage 50, the semicircular canals are complete. EYA1 localizes to the anterior aspect of the otocyst from stages 37 to 44. By stage 50, EYA1 distribution is localized primarily to the sensory maculae and the endolymphatic duct of the developing inner ear. Conclusions: Whole mount confocal imaging of the developing Xenopus inner ear delineates the exact timing of otic development, sensory cell differentiation, and innervation. EYA1 protein expression has a distinct distribution pattern at the anterior aspect of the developing otocyst in stages 41 and 44. Later stages have a more localized pattern, in which EYA1 is detected only in the sensory epithelium and endolymphatic duct. This specific pattern of expression indicates a possible role in the determination of the anterior-posterior orientation of the inner ear, as well as a later role in sensory cell differentiation.

scholarly journals The role of the chromatin remodeler Mi-2  in hematopoietic stem cell self-renewal and multilineage differentiation

2008 ◽  
Vol 22 (9) ◽  
pp. 1174-1189 ◽  
Author(s):  
T. Yoshida ◽  
I. Hazan ◽  
J. Zhang ◽  
S. Y. Ng ◽  
T. Naito ◽  
...  
Keyword(s):  
Stem Cell ◽  
Hematopoietic Stem Cell ◽  
Multilineage Differentiation ◽  
Chromatin Remodeler ◽  
Self Renewal ◽  
Hematopoietic Stem

The Role of the Endolymphatic Sac in Inner Ear Immunity

1987 ◽  
Vol 103 (5) ◽  
pp. 182-188 ◽  
Author(s):  
Shunichi Tomiyama ◽  
Jeffrey Harris
Keyword(s):  
Inner Ear ◽  
Endolymphatic Sac

MicroRNAs in Noise-Induced Hearing Loss and their Regulation by Oxidative Stress and Inflammation

2020 ◽  
Vol 21 (12) ◽  
pp. 1216-1224
Author(s):  
Fatemeh Forouzanfar ◽  
Samira Asgharzade
Keyword(s):  
Oxidative Stress ◽  
Hearing Loss ◽  
Hair Cell ◽  
Noise Exposure ◽  
Cell Damage ◽  
Sensory Cells ◽  
Noise Induced Hearing Loss ◽  
Irreversible Damage ◽  
Open Access Journals

Noise exposure (NE) has been recognized as one of the causes of sensorineural hearing loss (SNHL), which can bring about irreversible damage to sensory hair cells in the cochlea, through the launch of oxidative stress pathways and inflammation. Accordingly, determining the molecular mechanism involved in regulating hair cell apoptosis via NE is essential to prevent hair cell damage. However, the role of microRNAs (miRNAs) in the degeneration of sensory cells of the cochlea during NE has not been so far uncovered. Thus, the main purpose of this study was to demonstrate the regulatory role of miRNAs in the oxidative stress pathway and inflammation induced by NE. In this respect, articles related to noise-induced hearing loss (NIHL), oxidative stress, inflammation, and miRNA from various databases of Directory of Open Access Journals (DOAJ), Google Scholar, PubMed; Library, Information Science & Technology Abstracts (LISTA), and Web of Science were searched and retrieved. The findings revealed that several studies had suggested that up-regulation of miR-1229-5p, miR-451a, 185-5p, 186 and down-regulation of miRNA-96/182/183 and miR-30b were involved in oxidative stress and inflammation which could be used as biomarkers for NIHL. There was also a close relationship between NIHL and miRNAs, but further research is required to prove a causal association between miRNA alterations and NE, and also to determine miRNAs as biomarkers indicating responses to NE.

scholarly journals Dysregulation of protein kinase C in adult depression and suicide: evidence from postmortem brain studies

2021 ◽  
Author(s):  
Ghanshyam N Pandey ◽  
Anuradha Sharma ◽  
Hooriyah S Rizavi ◽  
Xinguo Ren
Keyword(s):  
Protein Kinase C ◽  
Protein Kinase ◽  
Protein Expression ◽  
Mrna Expression ◽  
Postmortem Brain ◽  
Cortical Region ◽  
Cytosol Fraction ◽  
Kinase C ◽  
Pkc Isozymes

Abstract Background Several lines of evidence suggest the abnormalities of protein kinase C (PKC) signaling system in mood disorders and suicide based primarily on the studies of PKC and its isozymes in the platelets and postmortem brain of depressed and suicidal subjects. In this study we examined the role of PKC isozymes in depression and suicide. Methods We determined the protein and mRNA expression of various PKC isozymes in the prefrontal cortical region [Brodmann area 9 (BA9)] in 24 normal control (NC) subjects, 24 depressed suicide (DS) subjects and 12 depressed non-suicide (DNS) subjects. The levels of mRNA in the prefrontal cortex (PFC) were determined by qRT-PCR and the protein expression was determined by Western blotting. Results We observed a significant decrease in mRNA expression of PKCα, PKCβI, PKCδ and PKCε and decreased protein expression either in the membrane or the cytosol fraction of PKC isozymes - PKCα, PKCβI, PKCβII and PKCδ in DS and DNS subjects compared with NC subjects. Conclusions The current study provides detailed evidence of specific dysregulation of certain PKC isozymes in the postmortem brain of DS and DNS subjects and further supports earlier evidence for the role of PKC in the platelets and brain of adult and teenage depressed and suicidal population. This comprehensive study may lead to further knowledge of the involvement of PKC in the pathophysiology of depression and suicide.

scholarly journals Local anesthetics impair the growth and self-renewal of glioblastoma stem cells by inhibiting ZDHHC15-mediated GP130 palmitoylation

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Xiaoqing Fan ◽  
Haoran Yang ◽  
Chenggang Zhao ◽  
Lizhu Hu ◽  
Delong Wang ◽  
...  
Keyword(s):  
Stem Cells ◽  
Western Blot ◽  
Local Anesthetics ◽  
Molecular Mechanisms ◽  
Biological Activities ◽  
Xenograft Model ◽  
Cell Counting ◽  
Migration And Invasion ◽  
Self Renewal

Abstract Background A large number of preclinical studies have shown that local anesthetics have a direct inhibitory effect on tumor biological activities, including cell survival, proliferation, migration, and invasion. There are few studies on the role of local anesthetics in cancer stem cells. This study aimed to determine the possible role of local anesthetics in glioblastoma stem cell (GSC) self-renewal and the underlying molecular mechanisms. Methods The effects of local anesthetics in GSCs were investigated through in vitro and in vivo assays (i.e., Cell Counting Kit 8, spheroidal formation assay, double immunofluorescence, western blot, and xenograft model). The acyl-biotin exchange method (ABE) assay was identified proteins that are S-acylated by zinc finger Asp-His-His-Cys-type palmitoyltransferase 15 (ZDHHC15). Western blot, co-immunoprecipitation, and liquid chromatograph mass spectrometer-mass spectrometry assays were used to explore the mechanisms of ZDHHC15 in effects of local anesthetics in GSCs. Results In this study, we identified a novel mechanism through which local anesthetics can damage the malignant phenotype of glioma. We found that local anesthetics prilocaine, lidocaine, procaine, and ropivacaine can impair the survival and self-renewal of GSCs, especially the classic glioblastoma subtype. These findings suggest that local anesthetics may weaken ZDHHC15 transcripts and decrease GP130 palmitoylation levels and membrane localization, thus inhibiting the activation of IL-6/STAT3 signaling. Conclusions In conclusion, our work emphasizes that ZDHHC15 is a candidate therapeutic target, and local anesthetics are potential therapeutic options for glioblastoma.

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