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1.
Development ; 147(15)2020 08 07.
Artigo em Inglês | MEDLINE | ID: mdl-32665247

RESUMO

Retinoic acid (RA), a vitamin A (retinol) derivative, has pleiotropic functions during embryonic development. The synthesis of RA requires two enzymatic reactions: oxidation of retinol into retinaldehyde by alcohol dehydrogenases (ADHs) or retinol dehydrogenases (RDHs); and oxidation of retinaldehyde into RA by aldehyde dehydrogenases family 1, subfamily A (ALDH1as), such as ALDH1a1, ALDH1a2 and ALDH1a3. Levels of RA in tissues are regulated by spatiotemporal expression patterns of genes encoding RA-synthesizing and -degrading enzymes, such as cytochrome P450 26 (Cyp26 genes). Here, we show that RDH10 is important for both sensory and non-sensory formation of the vestibule of the inner ear. Mice deficient in Rdh10 exhibit failure of utricle-saccule separation, otoconial formation and zonal patterning of vestibular sensory organs. These phenotypes are similar to those of Aldh1a3 knockouts, and the sensory phenotype is complementary to that of Cyp26b1 knockouts. Together, these results demonstrate that RDH10 and ALDH1a3 are the key RA-synthesis enzymes involved in vestibular development. Furthermore, we discovered that RA induces Cyp26b1 expression in the developing vestibular sensory organs, which generates the differential RA signaling required for zonal patterning.


Assuntos
Homeostase , Organogênese , Tretinoína/metabolismo , Vestíbulo do Labirinto/embriologia , Oxirredutases do Álcool/genética , Oxirredutases do Álcool/metabolismo , Animais , Camundongos , Camundongos Knockout , Retinal Desidrogenase/genética , Retinal Desidrogenase/metabolismo , Ácido Retinoico 4 Hidroxilase/genética , Ácido Retinoico 4 Hidroxilase/metabolismo , Vestíbulo do Labirinto/citologia
2.
Development ; 146(4)2019 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-30770380

RESUMO

The semicircular canals of the mammalian inner ear are derived from epithelial pouches in which epithelial cells in the central region of each pouch undergo resorption, leaving behind the region at the rim to form a tube-shaped canal. Lack of proliferation at the rim and/or over-clearing of epithelial cells in the center of the pouch can obliterate canal formation. Otic-specific knockout of bone morphogenetic protein 2 (Bmp2) results in absence of all three semicircular canals; however, the common crus and ampullae housing the sensory tissue (crista) are intact. The lack of Bmp2 causes Ntn1 (which encodes netrin 1), which is required for canal resorption, to be ectopically expressed at the canal rim. Ectopic Ntn1 results in reduction of Dlx5 and Lmo4, which are required for rim formation. These phenotypes can be partially rescued by removing one allele of Ntn1 in the Bmp2 mutants, indicating that Bmp2 normally negatively regulates Ntn1 for canal formation. Additionally, non-resorption of the canal pouch in Ntn1-/- mutants is partially rescued by removing one allele of Bmp2 Thus, reciprocal inhibition between Bmp2 and netrin 1 is involved in canal formation of the vestibule.


Assuntos
Proteína Morfogenética Óssea 2/genética , Regulação da Expressão Gênica no Desenvolvimento , Netrina-1/genética , Canais Semicirculares/embriologia , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Alelos , Animais , Proteína Morfogenética Óssea 2/metabolismo , Linhagem da Célula , Proliferação de Células , Fatores de Transcrição Forkhead/metabolismo , Perfilação da Expressão Gênica , Genótipo , Proteínas de Homeodomínio/metabolismo , Proteínas com Domínio LIM/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Mutação , Proteínas do Tecido Nervoso/metabolismo , Netrina-1/metabolismo , Fenótipo , Ligação Proteica , Domínios Proteicos , Vestíbulo do Labirinto/embriologia
3.
J Neurosci ; 38(23): 5429-5440, 2018 06 06.
Artigo em Inglês | MEDLINE | ID: mdl-29769265

RESUMO

LIM-domain containing transcription factors (LIM-TFs) are conserved factors important for embryogenesis. The specificity of these factors in transcriptional regulation is conferred by the complexes that they form with other proteins such as LIM-domain-binding (Ldb) proteins and LIM-domain only (LMO) proteins. Unlike LIM-TFs, these proteins do not bind DNA directly. LMO proteins are negative regulators of LIM-TFs and function by competing with LIM-TFs for binding to Ldb's. Although the LIM-TF Lmx1a is expressed in the developing mouse hindbrain, which provides many of the extrinsic signals for inner ear formation, conditional knock-out embryos of both sexes show that the inner ear source of Lmx1a is the major contributor of ear patterning. In addition, we have found that the reciprocal interaction between Lmx1a and Lmo4 (a LMO protein within the inner ear) mediates the formation of both vestibular and auditory structures. Lmo4 negatively regulates Lmx1a to form the three sensory cristae, the anterior semicircular canal, and the shape of the utricle in the vestibule. Furthermore, this negative regulation blocks ectopic sensory formation in the cochlea. In contrast, Lmx1a negatively regulates Lmo4 in mediating epithelial resorption of the canal pouch, which gives rise to the anterior and posterior semicircular canals. We also found that Lmx1a is independently required for the formation of the endolymphatic duct and hair cells in the basal cochlear region.SIGNIFICANCE STATEMENT The mammalian inner ear is a structurally complex organ responsible for detecting sound and maintaining balance. Failure to form the intricate 3D structure of this organ properly during development most likely will result in sensory deficits on some level. Here, we provide genetic evidence that a transcription factor, Lmx1a, interacts with its negative regulator, Lmo4, to pattern various vestibular and auditory components of the mammalian inner ear. Identifying these key molecules that mediate formation of this important sensory organ will be helpful for designing strategies and therapeutics to alleviate hearing loss and balance disorders.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Orelha Interna/embriologia , Proteínas com Domínio LIM/metabolismo , Proteínas com Homeodomínio LIM/metabolismo , Fatores de Transcrição/metabolismo , Animais , Camundongos , Camundongos Knockout
4.
Proc Natl Acad Sci U S A ; 112(12): 3746-51, 2015 Mar 24.
Artigo em Inglês | MEDLINE | ID: mdl-25775517

RESUMO

Sound frequency discrimination begins at the organ of Corti in mammals and the basilar papilla in birds. Both of these hearing organs are tonotopically organized such that sensory hair cells at the basal (proximal) end respond to high frequency sound, whereas their counterparts at the apex (distal) respond to low frequencies. Sonic hedgehog (Shh) secreted by the developing notochord and floor plate is required for cochlear formation in both species. In mice, the apical region of the developing cochlea, closer to the ventral midline source of Shh, requires higher levels of Shh signaling than the basal cochlea farther away from the midline. Here, gain-of-function experiments using Shh-soaked beads in ovo or a mouse model expressing constitutively activated Smoothened (transducer of Shh signaling) show up-regulation of apical genes in the basal cochlea, even though these regionally expressed genes are not necessarily conserved between the two species. In chicken, these altered gene expression patterns precede morphological and physiological changes in sensory hair cells that are typically associated with tonotopy such as the total number of stereocilia per hair cell and gene expression of an inward rectifier potassium channel, IRK1, which is a bona fide feature of apical hair cells in the basilar papilla. Furthermore, our results suggest that this conserved role of Shh in establishing cochlear tonotopy is initiated early in development by Shh emanating from the notochord and floor plate.


Assuntos
Cóclea/metabolismo , Audição/fisiologia , Proteínas Hedgehog/metabolismo , Mecanotransdução Celular , Animais , Galinhas , Cóclea/fisiologia , Células Ciliadas Auditivas/metabolismo , Camundongos , Notocorda/metabolismo , Órgão Espiral/metabolismo , Órgão Espiral/fisiologia , Fenótipo , Transdução de Sinais , Especificidade da Espécie
5.
PLoS Genet ; 11(3): e1005097, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25807530

RESUMO

Here we demonstrate association of variants in the mitochondrial asparaginyl-tRNA synthetase NARS2 with human hearing loss and Leigh syndrome. A homozygous missense mutation ([c.637G>T; p.Val213Phe]) is the underlying cause of nonsyndromic hearing loss (DFNB94) and compound heterozygous mutations ([c.969T>A; p.Tyr323*] + [c.1142A>G; p.Asn381Ser]) result in mitochondrial respiratory chain deficiency and Leigh syndrome, which is a neurodegenerative disease characterized by symmetric, bilateral lesions in the basal ganglia, thalamus, and brain stem. The severity of the genetic lesions and their effects on NARS2 protein structure cosegregate with the phenotype. A hypothetical truncated NARS2 protein, secondary to the Leigh syndrome mutation p.Tyr323* is not detectable and p.Asn381Ser further decreases NARS2 protein levels in patient fibroblasts. p.Asn381Ser also disrupts dimerization of NARS2, while the hearing loss p.Val213Phe variant has no effect on NARS2 oligomerization. Additionally we demonstrate decreased steady-state levels of mt-tRNAAsn in fibroblasts from the Leigh syndrome patients. In these cells we show that a decrease in oxygen consumption rates (OCR) and electron transport chain (ETC) activity can be rescued by overexpression of wild type NARS2. However, overexpression of the hearing loss associated p.Val213Phe mutant protein in these fibroblasts cannot complement the OCR and ETC defects. Our findings establish lesions in NARS2 as a new cause for nonsyndromic hearing loss and Leigh syndrome.


Assuntos
Aspartato-tRNA Ligase/genética , Doença de Leigh/genética , Aminoacil-RNA de Transferência/genética , Adulto , Sequência de Aminoácidos/genética , Animais , Aspartato-tRNA Ligase/biossíntese , Surdez/genética , Surdez/patologia , Orelha Interna/metabolismo , Orelha Interna/patologia , Feminino , Fibroblastos , Expressão Gênica/genética , Predisposição Genética para Doença , Humanos , Doença de Leigh/patologia , Masculino , Camundongos , Pessoa de Meia-Idade , Mitocôndrias/genética , Mitocôndrias/patologia , Mutação de Sentido Incorreto/genética , Consumo de Oxigênio/genética , Linhagem
6.
Dev Biol ; 414(1): 21-33, 2016 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-27083418

RESUMO

The inner ear is a complex organ comprised of various specialized sensory organs for detecting sound and head movements. The timing of specification for these sensory organs, however, is not clear. Previous fate mapping results of the inner ear indicate that vestibular and auditory ganglia and two of the vestibular sensory organs, the utricular macula (UM) and saccular macula (SM), are lineage related. Based on the medial-lateral relationship where respective auditory and vestibular neuroblasts exit from the otic epithelium and the subsequent formation of the medial SM and lateral UM in these regions, we hypothesized that specification of the two lateral structures, the vestibular ganglion and the UM are coupled and likewise for the two medial structures, the auditory ganglion and the SM. We tested this hypothesis by surgically inverting the primary axes of the otic cup in ovo and investigating the fate of the vestibular neurogenic region, which had been spotted with a lipophilic dye. Our results showed that the laterally-positioned, dye-associated, vestibular ganglion and UM were largely normal in transplanted ears, whereas both auditory ganglion and SM showed abnormalities suggesting the lateral but not the medial-derived structures were mostly specified at the time of transplantation. Both of these results are consistent with a temporal coupling between neuronal and macular fate specifications.


Assuntos
Nervo Coclear/citologia , Orelha Interna/embriologia , Células-Tronco Neurais/citologia , Neurogênese/fisiologia , Sáculo e Utrículo/citologia , Nervo Vestibular/citologia , Animais , Biomarcadores , Linhagem da Célula , Embrião de Galinha , Nervo Coclear/crescimento & desenvolvimento , Orelha Interna/transplante , Células Epiteliais/citologia , Regulação da Expressão Gênica no Desenvolvimento , Proteínas Luminescentes/análise , Sáculo e Utrículo/crescimento & desenvolvimento , Células Receptoras Sensoriais , Fatores de Tempo , Nervo Vestibular/crescimento & desenvolvimento
7.
Proc Natl Acad Sci U S A ; 110(34): 13869-74, 2013 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-23918393

RESUMO

Neural precursor cells of the central nervous system undergo successive temporal waves of terminal division, each of which is soon followed by the onset of cell differentiation. The organ of Corti in the mammalian cochlea develops differently, such that precursors at the apex are the first to exit from the cell cycle but the last to begin differentiating as mechanosensory hair cells. Using a tissue-specific knockout approach in mice, we show that this unique temporal pattern of sensory cell development requires that the adjacent auditory (spiral) ganglion serve as a source of the signaling molecule Sonic hedgehog (Shh). In the absence of this signaling, the cochlear duct is shortened, sensory hair cell precursors exit from the cell cycle prematurely, and hair cell differentiation closely follows cell cycle exit in a similar apical-to-basal direction. The dynamic relationship between the restriction of Shh expression in the developing spiral ganglion and its proximity to regions of the growing cochlear duct dictates the timing of terminal mitosis of hair cell precursors and their subsequent differentiation.


Assuntos
Pontos de Checagem do Ciclo Celular/fisiologia , Diferenciação Celular/fisiologia , Células Ciliadas Auditivas/fisiologia , Proteínas Hedgehog/metabolismo , Morfogênese/fisiologia , Órgão Espiral/embriologia , Gânglio Espiral da Cóclea/metabolismo , Animais , Desoxiuridina/análogos & derivados , Hibridização In Situ , Marcação In Situ das Extremidades Cortadas , Camundongos , Órgão Espiral/citologia
8.
Dev Biol ; 390(1): 51-67, 2014 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-24583262

RESUMO

Control over ionic composition and volume of the inner ear luminal fluid endolymph is essential for normal hearing and balance. Mice deficient in either the EphB2 receptor tyrosine kinase or the cognate transmembrane ligand ephrin-B2 (Efnb2) exhibit background strain-specific vestibular-behavioral dysfunction and signs of abnormal endolymph homeostasis. Using various loss-of-function mouse models, we found that Efnb2 is required for growth and morphogenesis of the embryonic endolymphatic epithelium, a precursor of the endolymphatic sac (ES) and duct (ED), which mediate endolymph homeostasis. Conditional inactivation of Efnb2 in early-stage embryonic ear tissues disrupted cell proliferation, cell survival, and epithelial folding at the origin of the endolymphatic epithelium. This correlated with apparent absence of an ED, mis-localization of ES ion transport cells relative to inner ear sensory organs, dysplasia of the endolymph fluid space, and abnormally formed otoconia (extracellular calcite-protein composites) at later stages of embryonic development. A comparison of Efnb2 and Notch signaling-deficient mutant phenotypes indicated that these two signaling systems have distinct and non-overlapping roles in ES/ED development. Homozygous deletion of the Efnb2 C-terminus caused abnormalities similar to those found in the conditional Efnb2 null homozygote. Analyses of fetal Efnb2 C-terminus deletion heterozygotes found mis-localized ES ion transport cells only in the genetic background exhibiting vestibular dysfunction. We propose that developmental dysplasias described here are a gene dose-sensitive cause of the vestibular dysfunction observed in EphB-Efnb2 signaling-deficient mice.


Assuntos
Orelha Interna/metabolismo , Saco Endolinfático/metabolismo , Efrina-B2/genética , Epitélio/metabolismo , Animais , Proliferação de Células , Sobrevivência Celular/genética , Orelha Interna/embriologia , Embrião de Mamíferos/citologia , Embrião de Mamíferos/embriologia , Embrião de Mamíferos/metabolismo , Saco Endolinfático/embriologia , Saco Endolinfático/ultraestrutura , Efrina-B2/metabolismo , Epitélio/embriologia , Epitélio/ultraestrutura , Feminino , Regulação da Expressão Gênica no Desenvolvimento , Hibridização In Situ , Camundongos , Camundongos da Linhagem 129 , Camundongos Endogâmicos C57BL , Camundongos Knockout , Microscopia Confocal , Microscopia Eletrônica de Varredura , Morfogênese/genética , Gravidez , Receptores Notch/genética , Receptores Notch/metabolismo , Transdução de Sinais/genética , Fatores de Tempo
9.
J Neurosci ; 33(9): 3879-90, 2013 Feb 27.
Artigo em Inglês | MEDLINE | ID: mdl-23447599

RESUMO

Sox2 is required for proper neuronal formation in the CNS, but the molecular mechanisms involved are not well characterized. Here, we addressed the role of Sox2 in neurogenesis of the developing chicken inner ear. Overexpressing Sox2 from a constitutive (ß-actin) promoter induces the expression of the proneural gene, Neurogenin1 (Ngn1); however, the expression of a downstream target of Ngn1, Neurod1, is unchanged. As a result, there is a reduction of neural precursors to delaminate and populate the developing cochleo-vestibular ganglion. In contrast, overexpression of either Ngn1 or Neurod1 is sufficient to promote the neural fate in this system. These results suggest that high levels of Sox2 inhibit progression of neurogenesis in the developing inner ear. Furthermore, we provide evidence that Ngn1 and Neurod1 inhibit Sox2 transcription through a phylogenetically conserved Sox2 enhancer to mediate neurogenesis. We propose that Sox2 confers neural competency by promoting Ngn1 expression, and that negative feedback inhibition of Sox2 by Ngn1 is an essential step in the progression from neural precursor to nascent neuron.


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Orelha Interna/citologia , Regulação da Expressão Gênica no Desenvolvimento/fisiologia , Proteínas do Tecido Nervoso/metabolismo , Neurogênese/fisiologia , Neurônios/fisiologia , Fatores de Transcrição SOXB1/metabolismo , Fatores Etários , Animais , Animais Geneticamente Modificados , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Contagem de Células , Embrião de Galinha , Orelha Interna/embriologia , Eletroporação , Regulação da Expressão Gênica no Desenvolvimento/genética , Proteínas de Fluorescência Verde/genética , Proteínas Luminescentes/genética , Camundongos , Proteínas do Tecido Nervoso/genética , Inibição Neural/genética , Neurogênese/genética , Fatores de Transcrição SOXB1/genética , Tubulina (Proteína)/metabolismo
10.
Proc Natl Acad Sci U S A ; 108(1): 161-6, 2011 Jan 04.
Artigo em Inglês | MEDLINE | ID: mdl-21173260

RESUMO

Vertebrate hearing and balance are based in complex asymmetries of inner ear structure. Here, we identify retinoic acid (RA) as an extrinsic signal that acts directly on the ear rudiment to affect its compartmentalization along the anterior-posterior axis. A rostrocaudal wave of RA activity, generated by tissues surrounding the nascent ear, induces distinct responses from anterior and posterior halves of the inner ear rudiment. Prolonged response to RA by posterior otic tissue correlates with Tbx1 transcription and formation of mostly nonsensory inner ear structures. By contrast, anterior otic tissue displays only a brief response to RA and forms neuronal elements and most sensory structures of the inner ear.


Assuntos
Padronização Corporal/fisiologia , Orelha Interna/embriologia , Regulação da Expressão Gênica no Desenvolvimento/fisiologia , Transdução de Sinais/fisiologia , Proteínas com Domínio T/metabolismo , Tretinoína/metabolismo , Animais , Embrião de Galinha , Cicloeximida , Regulação da Expressão Gênica no Desenvolvimento/genética , Hibridização In Situ , Camundongos , Microesferas , beta-Galactosidase
11.
Dev Biol ; 362(2): 172-86, 2012 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-22182523

RESUMO

Development of the mammalian inner ear requires coordination of cell proliferation, cell fate determination and morphogenetic movements. While significant progress has been made in identifying developmental signals required for inner ear formation, less is known about how distinct signals are coordinated by their downstream mediators. Members of the Rac family of small GTPases are known regulators of cytoskeletal remodeling and numerous other cellular processes. However, the function of Rac GTPases in otic development is largely unexplored. Here, we show that Rac1 and Rac3 redundantly regulate many aspects of inner ear morphogenesis. While no morphological defects were observed in Rac3(-/-) mice, Rac1(CKO); Rac3(-/-) double mutants displayed enhanced vestibular and cochlear malformations compared to Rac1(CKO) single mutants. Moreover, in Rac1(CKO); Rac3(-/-) mutants, we observed compromised E-cadherin-mediated cell adhesion, reduced cell proliferation and increased cell death in the early developing otocyst, leading to a decreased size and malformation of the membranous labyrinth. Finally, cochlear extension was severely disrupted in Rac1(CKO); Rac3(-/-) mutants, accompanied by a loss of epithelial cohesion and formation of ectopic sensory patches underneath the cochlear duct. The compartmentalized expression of otic patterning genes within the Rac1(CKO); Rac3(-/-) mutant otocyst was largely normal, however, indicating that Rac proteins regulate inner ear morphogenesis without affecting cell fate specification. Taken together, our results reveal an essential role for Rac GTPases in coordinating cell adhesion, cell proliferation, cell death and cell movements during otic development.


Assuntos
Orelha Interna/embriologia , Morfogênese/genética , Neuropeptídeos/metabolismo , Proteínas rac de Ligação ao GTP/metabolismo , Animais , Apoptose/genética , Caderinas/metabolismo , Adesão Celular/genética , Proliferação de Células , Orelha Interna/metabolismo , Orelha Interna/patologia , Galactosídeos , Imuno-Histoquímica , Hibridização In Situ , Indóis , Camundongos , Camundongos Knockout , Microscopia Eletrônica de Varredura , Morfogênese/fisiologia , Neuropeptídeos/genética , Proteínas rac de Ligação ao GTP/genética , Proteínas rac1 de Ligação ao GTP
12.
Nat Commun ; 13(1): 6330, 2022 10 24.
Artigo em Inglês | MEDLINE | ID: mdl-36280667

RESUMO

Otolith organs of the inner ear are innervated by two parallel afferent projections to the brainstem and cerebellum. These innervations were proposed to segregate across the line of polarity reversal (LPR) within each otolith organ, which divides the organ into two regions of hair cells (HC) with opposite stereociliary orientation. The relationship and functional significance of these anatomical features are not known. Here, we show regional expression of Emx2 in otolith organs, which establishes LPR, mediates the neuronal segregation across LPR and constitutes the bidirectional sensitivity function. Conditional knockout (cKO) of Emx2 in HCs lacks LPR. Tmie cKO, in which mechanotransduction was abolished selectively in HCs within the Emx2 expression domain also lacks bidirectional sensitivity. Analyses of both mutants indicate that LPR is specifically required for mice to swim comfortably and to traverse a balance beam efficiently, but LPR is not required for mice to stay on a rotating rod.


Assuntos
Proteínas de Homeodomínio , Mecanotransdução Celular , Membrana dos Otólitos , Fatores de Transcrição , Animais , Camundongos , Células Ciliadas Auditivas/fisiologia , Membrana dos Otólitos/fisiologia , Sáculo e Utrículo/fisiologia , Fatores de Transcrição/genética , Proteínas de Homeodomínio/genética
13.
Dev Biol ; 337(2): 324-34, 2010 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-19896934

RESUMO

A mature inner ear is a complex structure consisting of vestibular and auditory components. Microsurgical ablations, rotations, and translocations were performed in ovo to identify the tissues that control inner ear morphogenesis. We show that mesenchyme/ectoderm adjacent to the developing ear specifically governs the shape of vestibular components - the semicircular canals and ampullae - by conferring anteroposterior axial information to these structures. In contrast, removal of individual hindbrain rhombomeres adjacent to the developing ear preferentially affects the growth and morphogenesis of the auditory subdivision, the cochlear duct, or basilar papilla. Removal of rhombomere 5 affects cochlear duct growth, while rhombomere 6 removal affects cochlear growth and morphogenesis. Rotating rhombomeres 5 and 6 along the anteroposterior axis also impacts cochlear duct morphogenesis but has little effect on the vestibular components. Our studies indicate that discrete tissues, acting at a distance, control the morphogenesis of distinct elements of the inner ear. These results provide a basis for identifying factors that are essential to vestibular and auditory development in vertebrates.


Assuntos
Orelha Interna/embriologia , Mesoderma/embriologia , Morfogênese , Rombencéfalo/embriologia , Animais , Padronização Corporal , Embrião de Galinha , Galinhas , Ducto Coclear/embriologia , Mesoderma/transplante , Notocorda/embriologia , Tamanho do Órgão
14.
PLoS Genet ; 4(4): e1000050, 2008 Apr 11.
Artigo em Inglês | MEDLINE | ID: mdl-18404215

RESUMO

Angular head movements in vertebrates are detected by the three semicircular canals of the inner ear and their associated sensory tissues, the cristae. Bone morphogenetic protein 4 (Bmp4), a member of the Transforming growth factor family (TGF-beta), is conservatively expressed in the developing cristae in several species, including zebrafish, frog, chicken, and mouse. Using mouse models in which Bmp4 is conditionally deleted within the inner ear, as well as chicken models in which Bmp signaling is knocked down specifically in the cristae, we show that Bmp4 is essential for the formation of all three cristae and their associated canals. Our results indicate that Bmp4 does not mediate the formation of sensory hair and supporting cells within the cristae by directly regulating genes required for prosensory development in the inner ear such as Serrate1 (Jagged1 in mouse), Fgf10, and Sox2. Instead, Bmp4 most likely mediates crista formation by regulating Lmo4 and Msx1 in the sensory region and Gata3, p75Ngfr, and Lmo4 in the non-sensory region of the crista, the septum cruciatum. In the canals, Bmp2 and Dlx5 are regulated by Bmp4, either directly or indirectly. Mechanisms involved in the formation of sensory organs of the vertebrate inner ear are thought to be analogous to those regulating sensory bristle formation in Drosophila. Our results suggest that, in comparison to sensory bristles, crista formation within the inner ear requires an additional step of sensory and non-sensory fate specification.


Assuntos
Proteínas Morfogenéticas Ósseas/fisiologia , Movimentos da Cabeça/fisiologia , Vestíbulo do Labirinto/embriologia , Vestíbulo do Labirinto/fisiologia , Animais , Animais Geneticamente Modificados , Proteína Morfogenética Óssea 4 , Proteínas Morfogenéticas Ósseas/deficiência , Proteínas Morfogenéticas Ósseas/genética , Proteínas de Transporte/genética , Proteínas de Transporte/fisiologia , Embrião de Galinha , Regulação para Baixo , Feminino , Fatores de Transcrição Forkhead/genética , Fatores de Transcrição Forkhead/fisiologia , Regulação da Expressão Gênica no Desenvolvimento , Masculino , Camundongos , Camundongos Knockout , Camundongos Mutantes , Camundongos Transgênicos , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/fisiologia , Fenótipo , Equilíbrio Postural/fisiologia , Gravidez , Canais Semicirculares/embriologia , Canais Semicirculares/fisiologia , Ductos Semicirculares/embriologia , Ductos Semicirculares/fisiologia , Transdução de Sinais , Proteína Smad6/genética , Proteína Smad6/fisiologia , Proteínas de Peixe-Zebra
15.
Dev Dyn ; 239(2): 505-13, 2010 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-20063299

RESUMO

The mammalian organ of Corti of the inner ear is a highly sophisticated sensory end organ responsible for detecting sound. Noggin is a secreted glycoprotein, which antagonizes bone morphogenetic proteins 2 and 4 (Bmp2 and Bmp4). The lack of this antagonist causes increased rows of inner and outer hair cells in the organ of Corti. In mice, Bmp2 is expressed transiently in nascent cochlear hair cells. To investigate whether Noggin normally modulates the levels of Bmp2 for hair cell formation, we deleted Bmp2 in the cochlear hair cells using two cre strains, Foxg1(cre/+) and Gfi1(cre/+). Bmp2 conditional knockout cochleae generated using these two cre strains show normal hair cells. Furthermore, Gfi1(cre/+);Bmp2(lox/-) mice are viable and have largely normal hearing. The combined results of Noggin and Bmp2 mutants suggest that Noggin is likely to regulate other Bmps in the cochlea such as Bmp4.


Assuntos
Proteína Morfogenética Óssea 2/metabolismo , Proteína Morfogenética Óssea 4/metabolismo , Proteínas de Transporte/metabolismo , Órgão Espiral/embriologia , Animais , Proteína Morfogenética Óssea 2/genética , Proteína Morfogenética Óssea 4/genética , Proteínas de Transporte/genética , Proteínas de Ligação a DNA/genética , Potenciais Evocados Auditivos do Tronco Encefálico , Fatores de Transcrição Forkhead/genética , Regulação da Expressão Gênica no Desenvolvimento , Audição , Integrases , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas do Tecido Nervoso/genética , Órgão Espiral/metabolismo , Presbiacusia/genética , Presbiacusia/metabolismo , Fatores de Transcrição/genética
16.
Dev Biol ; 333(1): 14-25, 2009 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-19540218

RESUMO

Lmx1a is a LIM homeodomain-containing transcription factor, which is required for the formation of multiple organs. Lmx1a is broadly expressed in early stages of the developing inner ear, but its expression is soon restricted to the non-sensory regions of the developing ear. In an Lmx1a functional null mutant, dreher (dr(J)/dr(J)), the inner ears lack a non-sensory structure, the endolymphatic duct, and the membranous labyrinth is poorly developed. These phenotypes are consistent with Lmx1a's role as a selector gene. More importantly, while all three primary fates of the inner ear - neural, sensory, and non-sensory - are specified in dr(J)/dr(J), normal boundaries among these tissues are often violated. For example, the neurogenic domain of the ear epithelium, from which cells delaminate to form the cochleovestibular ganglion, is expanded. Within the neurogenic domain, the demarcation between the vestibular and auditory neurogenic domains is most likely disrupted as well, based on the increased numbers of vestibular neuroblasts and ectopic expression of Fgf3, which normally is associated specifically with the vestibular neurogenic region. Furthermore, aberrant and ectopic sensory organs are observed; most striking among these is vestibular-like hair cells located in the cochlear duct.


Assuntos
Orelha Interna/embriologia , Proteínas de Homeodomínio/fisiologia , Animais , Padronização Corporal , Ducto Coclear/embriologia , Ducto Coclear/inervação , Ducto Coclear/metabolismo , Orelha Interna/anormalidades , Orelha Interna/metabolismo , Epitélio/embriologia , Epitélio/inervação , Epitélio/metabolismo , Proteínas de Homeodomínio/biossíntese , Proteínas de Homeodomínio/genética , Proteínas com Homeodomínio LIM , Camundongos , Camundongos Mutantes , Mutação , Gânglio Espiral da Cóclea/anormalidades , Gânglio Espiral da Cóclea/embriologia , Fatores de Transcrição , Vestíbulo do Labirinto/embriologia , Vestíbulo do Labirinto/inervação , Vestíbulo do Labirinto/metabolismo
17.
Hum Mol Genet ; 17(6): 844-53, 2008 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-18096605

RESUMO

Conductive hearing loss occurs when sound waves are not relayed efficiently to the inner ear. Mutations of the NOGGIN (NOG) gene in humans are associated with several autosomal dominant disorders such as proximal symphalangism and multiple synostoses. These syndromes are characterized by skeletal defects and synostoses, which include conductive hearing loss. Noggin is an antagonist of bone morphogenetic proteins (BMPs), and balanced levels of BMPs and Noggin are required for proper skeletal formation. Depending on the genetic background, some of the Nog(+/-) mice display mild hearing loss, that is, conductive in nature. Since Noggin is a single exon gene, this data strongly suggest that the autosomal dominant disorders associated with NOG mutations are due to haploinsufficiency of NOGGIN. The conductive hearing loss in Nog(+/-) mice is caused by an ectopic bone bridge located between the stapes and the posterior wall of the tympanum, which affects the normal mobility of the ossicle. Our analyses suggest that the ectopic bone formation is caused by a failure of the stapes and styloid process to separate completely during development. This failure of bone separation in the Nog(+/-) mice reveals another consequence of chondrocyte hyperplasia due to unopposed Bmp activities in these mutants such as Bmp4 and Bmp14 (Gdf5). More importantly, these results establish Nog(+/-) mice as the first animal model for the study of conductive rather than neurosensory hearing loss that has direct relevance to human genetic disorders.


Assuntos
Proteínas de Transporte/genética , Modelos Animais de Doenças , Perda Auditiva Condutiva/congênito , Heterozigoto , Animais , Proteínas Morfogenéticas Ósseas/metabolismo , Perda Auditiva Condutiva/genética , Perda Auditiva Condutiva/fisiopatologia , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Limiar Sensorial
18.
Dev Dyn ; 238(11): 2725-34, 2009 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-19842177

RESUMO

The vestibular portion of the inner ear, the three semicircular canals and their sensory cristae, is responsible for detecting angular head movements. It was proposed that sensory cristae induce formation of their non-sensory components, the semicircular canals. Here, we analyzed the inner ears of Foxg1(-/-) mouse mutants, which display vestibular defects that are in conflict with the above model. In Foxg1(-/-) ears, the lateral canal is present without the lateral ampulla, which houses the lateral crista. Our gene expression analyses indicate that at the time when canal specification is thought to occur, the prospective lateral crista is present, which could have induced lateral canal formation prior to its demise. Our genetic fate-mapping analyses indicate an improper separation between anterior and lateral cristae in Foxg1(-/-) mutants. Our data further suggest that a function of Foxg1 in the inner ear is to restrict sensory fate.


Assuntos
Proteína Morfogenética Óssea 2/metabolismo , Fatores de Transcrição Forkhead/metabolismo , Proteínas de Homeodomínio/metabolismo , Morfogênese , Proteínas do Tecido Nervoso/metabolismo , Ductos Semicirculares/embriologia , Fatores de Transcrição/metabolismo , Proteínas Adaptadoras de Transdução de Sinal , Animais , Fatores de Transcrição Forkhead/genética , Regulação da Expressão Gênica no Desenvolvimento/genética , Regulação da Expressão Gênica no Desenvolvimento/fisiologia , Proteínas com Domínio LIM , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas do Tecido Nervoso/genética , Fenótipo , Ductos Semicirculares/anatomia & histologia , Ductos Semicirculares/metabolismo
19.
Elife ; 92020 09 23.
Artigo em Inglês | MEDLINE | ID: mdl-32965215

RESUMO

Directional sensitivity of hair cells (HCs) is conferred by the aymmetric apical hair bundle, comprised of a kinocilium and stereocilia staircase. The mother centriole (MC) forms the base of the kinocilium and the stereocilia develop adjacent to it. Previously, we showed that transcription factor Emx2 reverses hair bundle orientation and its expression in the mouse vestibular utricle is restricted, resulting in two regions of opposite bundle orientation (Jiang et al., 2017). Here, we investigated establishment of opposite bundle orientation in embryonic utricles by live-imaging GFP-labeled centrioles in HCs. The daughter centriole invariably migrated ahead of the MC from the center to their respective peripheral locations in HCs. Comparing HCs between utricular regions, centriole trajectories were similar but they migrated toward opposite directions, suggesting that Emx2 pre-patterned HCs prior to centriole migration. Ectopic Emx2, however, reversed centriole trajectory within hours during a critical time-window when centriole trajectory was responsive to Emx2.


Assuntos
Polaridade Celular/fisiologia , Células Ciliadas Auditivas , Proteínas de Homeodomínio/metabolismo , Sáculo e Utrículo , Fatores de Transcrição/metabolismo , Animais , Centríolos/metabolismo , Cílios/metabolismo , Feminino , Células Ciliadas Auditivas/citologia , Células Ciliadas Auditivas/metabolismo , Proteínas de Homeodomínio/genética , Masculino , Camundongos , Camundongos Knockout , Microscopia , Sáculo e Utrículo/citologia , Sáculo e Utrículo/diagnóstico por imagem , Sáculo e Utrículo/metabolismo , Fatores de Transcrição/genética
20.
Elife ; 92020 12 30.
Artigo em Inglês | MEDLINE | ID: mdl-33377867

RESUMO

Each hair cell (HC) precursor of zebrafish neuromasts divides to form two daughter HCs of opposite hair bundle orientations. Previously, we showed that transcription factor Emx2, expressed in only one of the daughter HCs, generates this bidirectional HC pattern (Jiang et al., 2017). Here, we asked whether Emx2 mediates this effect by changing location of hair bundle establishment or positions of HCs since daughter HCs are known to switch positions with each other. We showed this HC rearrangement, redefined as two processes named Rock and Roll, is required for positional acquisition of HCs. Apical protrusion formation of nascent HCs and planar polarity signaling are both important for the Rock and Roll. Emx2 facilitates Rock and Roll by delaying apical protrusion of its nascent HCs but it does not determine HCs' ultimate positions, indicating that Emx2 mediates bidirectional HC pattern by changing the location where hair bundle is established in HCs.


Assuntos
Regulação da Expressão Gênica no Desenvolvimento/fisiologia , Células Ciliadas Auditivas/metabolismo , Proteínas de Homeodomínio/metabolismo , Fatores de Transcrição/metabolismo , Animais , Polaridade Celular/fisiologia , Sistema da Linha Lateral/fisiologia , Peixe-Zebra/metabolismo
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