Two regulatory genes, cNkx5-1 and cPax2, show different responses to local signals during otic placode and vesicle formation in the chick embryo

H. Herbrand; S. Guthrie; T. Hadrys; S. Hoffmann; H.H. Arnold; S. Rinkwitz-Brandt; E. Bober

doi:10.1242/dev.125.4.645

Two regulatory genes, cNkx5-1 and cPax2, show different responses to local signals during otic placode and vesicle formation in the chick embryo

Development ◽

10.1242/dev.125.4.645 ◽

1998 ◽

Vol 125 (4) ◽

pp. 645-654 ◽

Cited By ~ 7

Author(s):

H. Herbrand ◽

S. Guthrie ◽

T. Hadrys ◽

S. Hoffmann ◽

H.H. Arnold ◽

...

Keyword(s):

Expression Pattern ◽

Homeobox Gene ◽

Lateral Wall ◽

Otic Vesicle ◽

Ear Development ◽

Inner Ear Development ◽

Dynamic Expression ◽

Otic Placode ◽

Transplantation Experiments ◽

Correct Expression

The early stages of otic placode development depend on signals from neighbouring tissues including the hindbrain. The identity of these signals and of the responding placodal genes, however, is not known. We have identified a chick homeobox gene cNkx5-1, which is expressed in the otic placode beginning at stage 10 and exhibits a dynamic expression pattern during formation and further differentiation of the otic vesicle. In a series of heterotopic transplantation experiments, we demonstrate that cNkx5-1 can be activated in ectopic positions. However, significant differences in otic development and cNkx5-1 gene activity were observed when placodes were transplanted into the more rostral positions within the head mesenchyme or into the wing buds of older hosts. These results indicate that only the rostral tissues were able to induce and/or maintain ear development. Ectopically induced cNkx5-1 expression always reproduced the endogenous pattern within the lateral wall of the otocyst that is destined to form vestibular structures. In contrast, cPax2 which is expressed in the medial wall of the early otic vesicle later forming the cochlea never resumed its correct expression pattern after transplantation. Our experiments illustrate that only some aspects of gene expression and presumably pattern formation during inner ear development can be established and maintained ectopically. In particular, the dorsal vestibular structures seem to be programmed earlier and differently from the ventral cochlear part.

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Nkx5-1 controls semicircular canal formation in the mouse inner ear

Development ◽

10.1242/dev.125.1.33 ◽

1998 ◽

Vol 125 (1) ◽

pp. 33-39 ◽

Cited By ~ 5

Author(s):

T. Hadrys ◽

T. Braun ◽

S. Rinkwitz-Brandt ◽

H.H. Arnold ◽

E. Bober

Keyword(s):

Homologous Recombination ◽

Inner Ear ◽

Homeobox Gene ◽

Semicircular Canals ◽

Otic Vesicle ◽

Null Mutation ◽

Complex Structures ◽

Vestibular Organ ◽

Inner Ear Development ◽

Vestibular Organs

The inner ear develops from the otic vesicle, a one-cell-thick epithelium, which eventually transforms into highly complex structures including the sensory organs for balance (vestibulum) and hearing (cochlea). Several mouse inner ear mutations with hearing and balance defects have been described but for most the underlying genes have not been identified, for example, the genes controlling the development of the vestibular organs. Here, we report the inactivation of the homeobox gene, Nkx5-1, by homologous recombination in mice. This gene is expressed in vestibular structures throughout inner ear development. Mice carrying the Nkx5-1 null mutation exhibit behavioural abnormalities that resemble the typical hyperactivity and circling movements of the shaker/waltzer type mutants. The balance defect correlates with severe malformations of the vestibular organ in Nkx5-1(−/−) mutants, which fail to develop the semicircular canals. Nkx5-1 is the first ear-specific molecule identified to play a crucial role in the formation of the mammalian vestibular system.

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Dlx5 regulates regional development of the branchial arches and sensory capsules

Development ◽

10.1242/dev.126.17.3831 ◽

1999 ◽

Vol 126 (17) ◽

pp. 3831-3846 ◽

Cited By ~ 20

Author(s):

M.J. Depew ◽

J.K. Liu ◽

J.E. Long ◽

R. Presley ◽

J.J. Meneses ◽

...

Keyword(s):

Homeobox Gene ◽

Semicircular Canals ◽

Otic Vesicle ◽

Craniofacial Malformations ◽

General Role ◽

Targeted Deletion ◽

Mandibular Arch ◽

Branchial Arches ◽

Otic Placode ◽

The Right

We report the generation and analysis of mice homozygous for a targeted deletion of the Dlx5 homeobox gene. Dlx5 mutant mice have multiple defects in craniofacial structures, including their ears, noses, mandibles and calvaria, and die shortly after birth. A subset (28%) exhibit exencephaly. Ectodermal expression of Dlx5 is required for the development of olfactory and otic placode-derived epithelia and surrounding capsules. The nasal capsules are hypoplastic (e.g. lacking turbinates) and, in most cases, the right side is more severely affected than the left. Dorsal otic vesicle derivatives (e. g. semicircular canals and endolymphatic duct) and the surrounding capsule, are more severely affected than ventral (cochlear) structures. Dlx5 is also required in mandibular arch ectomesenchyme, as the proximal mandibular arch skeleton is dysmorphic. Dlx5 may control craniofacial development in part through the regulation of the goosecoid homeobox gene. goosecoid expression is greatly reduced in Dlx5 mutants, and both goosecoid and Dlx5 mutants share a number of similar craniofacial malformations. Dlx5 may perform a general role in skeletal differentiation, as exemplified by hypomineralization within the calvaria. The distinct focal defects within the branchial arches of the Dlx1, Dlx2 and Dlx5 mutants, along with the nested expression of their RNAs, support a model in which these genes have both redundant and unique functions in the regulation of regional patterning of the craniofacial ectomesenchyme.

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Differential and overlapping expression pattern of SOX2 and SOX9 in inner ear development

Gene Expression Patterns ◽

10.1016/j.gep.2009.04.003 ◽

2009 ◽

Vol 9 (6) ◽

pp. 444-453 ◽

Cited By ~ 45

Author(s):

Angel C.Y. Mak ◽

Irene Y.Y. Szeto ◽

Bernd Fritzsch ◽

Kathryn S.E. Cheah

Keyword(s):

Inner Ear ◽

Expression Pattern ◽

Ear Development ◽

Inner Ear Development

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Early steps in inner ear development: induction and morphogenesis of the otic placode

Frontiers in Pharmacology ◽

10.3389/fphar.2015.00019 ◽

2015 ◽

Vol 6 ◽

Cited By ~ 20

Author(s):

Xiaorei Sai ◽

Raj K. Ladher

Keyword(s):

Inner Ear ◽

Ear Development ◽

Inner Ear Development ◽

Otic Placode

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A Gata3 3′ Distal Otic Vesicle Enhancer Directs Inner Ear-Specific Gata3 Expression

Molecular and Cellular Biology ◽

10.1128/mcb.00302-18 ◽

2018 ◽

Vol 38 (21) ◽

Cited By ~ 5

Author(s):

Takashi Moriguchi ◽

Tomofumi Hoshino ◽

Arvind Rao ◽

Lei Yu ◽

Jun Takai ◽

...

Keyword(s):

Inner Ear ◽

Semicircular Canal ◽

Regulatory Element ◽

Spiral Ganglion ◽

Otic Vesicle ◽

Regulatory Activity ◽

Specific Expression ◽

Ear Development ◽

Inner Ear Development ◽

Gata3 Expression

ABSTRACT Transcription factor GATA3 plays vital roles in inner ear development, while regulatory mechanisms controlling its inner ear-specific expression are undefined. We demonstrate that a cis-regulatory element lying 571 kb 3′ to the Gata3 gene directs inner ear-specific Gata3 expression, which we refer to as the Gata3 otic vesicle enhancer (OVE). In transgenic murine embryos, a 1.5-kb OVE-directed lacZ reporter (TgOVE-LacZ) exhibited robust lacZ expression specifically in the otic vesicle (OV), an inner ear primordial tissue, and its derivative semicircular canal. To further define the regulatory activity of this OVE, we generated Cre transgenic mice in which Cre expression was directed by a 246-bp core sequence within the OVE element (TgcoreOVE-Cre). TgcoreOVE-Cre successfully marked the OV-derived inner ear tissues, including cochlea, semicircular canal and spiral ganglion, when crossed with ROSA26 lacZ reporter mice. Furthermore, Gata3 conditionally mutant mice, when crossed with the TgcoreOVE-Cre, showed hypoplasia throughout the inner ear tissues. These results demonstrate that OVE has a sufficient regulatory activity to direct Gata3 expression specifically in the otic vesicle and semicircular canal and that Gata3 expression driven by the OVE is crucial for normal inner ear development.

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Embryonic Origins of Virus-Induced Hearing Loss: Overview of Molecular Etiology

Viruses ◽

10.3390/v13010071 ◽

2021 ◽

Vol 13 (1) ◽

pp. 71

Author(s):

Maryam Karimi-Boroujeni ◽

Ali Zahedi-Amiri ◽

Kevin M. Coombs

Keyword(s):

Hearing Loss ◽

Inner Ear ◽

Molecular Mechanisms ◽

Primary Root ◽

World Health ◽

Otic Vesicle ◽

Molecular Characteristics ◽

Ear Development ◽

Inner Ear Development ◽

Acquired Hearing Loss

Hearing loss, one of the most prevalent chronic health conditions, affects around half a billion people worldwide, including 34 million children. The World Health Organization estimates that the prevalence of disabling hearing loss will increase to over 900 million people by 2050. Many cases of congenital hearing loss are triggered by viral infections during different stages of pregnancy. However, the molecular mechanisms by which viruses induce hearing loss are not sufficiently explored, especially cases that are of embryonic origins. The present review first describes the cellular and molecular characteristics of the auditory system development at early stages of embryogenesis. These developmental hallmarks, which initiate upon axial specification of the otic placode as the primary root of the inner ear morphogenesis, involve the stage-specific regulation of several molecules and pathways, such as retinoic acid signaling, Sonic hedgehog, and Wnt. Different RNA and DNA viruses contributing to congenital and acquired hearing loss are then discussed in terms of their potential effects on the expression of molecules that control the formation of the auditory and vestibular compartments following otic vesicle differentiation. Among these viruses, cytomegalovirus and herpes simplex virus appear to have the most effect upon initial molecular determinants of inner ear development. Moreover, of the molecules governing the inner ear development at initial stages, SOX2, FGFR3, and CDKN1B are more affected by viruses causing either congenital or acquired hearing loss. Abnormalities in the function or expression of these molecules influence processes like cochlear development and production of inner ear hair and supporting cells. Nevertheless, because most of such virus–host interactions were studied in unrelated tissues, further validations are needed to confirm whether these viruses can mediate the same effects in physiologically relevant models simulating otic vesicle specification and growth.

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Ceramide Kinase Inhibition Blocks IGF-1-Mediated Survival of Otic Neurosensory Progenitors by Impairing AKT Phosphorylation

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.678760 ◽

2021 ◽

Vol 9 ◽

Author(s):

Yolanda León ◽

Marta Magariños ◽

Isabel Varela-Nieto

Keyword(s):

Inner Ear ◽

Central Element ◽

Specific Inhibitor ◽

Otic Vesicle ◽

Developmentally Regulated ◽

Ear Development ◽

Akt Phosphorylation ◽

Ceramide Kinase ◽

Inner Ear Development ◽

Key Factor

Sphingolipids are bioactive lipid components of cell membranes with important signal transduction functions in health and disease. Ceramide is the central building block for sphingolipid biosynthesis and is processed to form structurally and functionally distinct sphingolipids. Ceramide can be phosphorylated by ceramide kinase (CERK) to generate ceramide-1-phosphate, a cytoprotective signaling molecule that has been widely studied in multiple tissues and organs, including the developing otocyst. However, little is known about ceramide kinase regulation during inner ear development. Using chicken otocysts, we show that genes for CERK and other enzymes of ceramide metabolism are expressed during the early stages of inner ear development and that CERK is developmentally regulated at the otic vesicle stage. To explore its role in inner ear morphogenesis, we blocked CERK activity in organotypic cultures of otic vesicles with a specific inhibitor. Inhibition of CERK activity impaired proliferation and promoted apoptosis of epithelial otic progenitors. CERK inhibition also compromised neurogenesis of the acoustic-vestibular ganglion. Insulin-like growth factor-1 (IGF-1) is a key factor for proliferation, survival and differentiation in the chicken otocyst. CERK inhibition decreased IGF-1-induced AKT phosphorylation and blocked IGF-1-induced cell survival. Overall, our data suggest that CERK is activated as a central element in the network of anti-apoptotic pro-survival pathways elicited by IGF-1 during early inner ear development.

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