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Andrew K Groves

Publications and source records attributed to Andrew K Groves.

10 recordsLinked to original sources
PubMed2006

Mammalian cochlear supporting cells can divide and trans-differentiate into hair cells.

Sensory hair cells of the mammalian organ of Corti in the inner ear do not regenerate when lost as a consequence of injury, disease, or age-related deafness. This contrasts with other vertebrates such as birds, where the death of hair cells causes surrounding supporting cells to re-enter the cell cycle and give rise to both new hair cells and supporting cells. It is not clear whether the lack of mammalian hair cell regeneration is due to an intrinsic inability of supporting cells to divide and differentiate or to an absence or blockade of regenerative signals. Here we show that post-mitotic supporting cells purified from the postnatal mouse cochlea retain the ability to divide and trans-differentiate into new hair cells in culture. Furthermore, we show that age-dependent changes in supporting cell proliferative capacity are due in part to changes in the ability to downregulate the cyclin-dependent kinase inhibitor p27(Kip1) (also known as Cdkn1b). These results indicate that postnatal mammalian supporting cells are potential targets for therapeutic manipulation.

Animals↗
PubMed2006

Tissue-specific roles of Tbx1 in the development of the outer, middle and inner ear, defective in 22q11DS patients.

Most 22q11.2 deletion syndrome (22q11DS) patients have middle and outer ear anomalies, whereas some have inner ear malformations. Tbx1, a gene hemizygously deleted in 22q11DS patients and required for ear development, is expressed in multiple tissues during embryogenesis. To determine the role of Tbx1 in the first pharyngeal pouch (PPI) in forming outer and middle ears, we tissue-specifically inactivated the gene using Foxg1-Cre. In the conditional mutants, PPI failed to outgrow, preventing the middle ear bone condensations from forming. Tbx1 was also inactivated in the otic vesicle (OV), resulting in the failure of inner ear sensory organ formation, and in duplication of the cochleovestibular ganglion (CVG). Consistent with the anatomical defects, the sensory genes, Otx1 and Bmp4 were downregulated, whereas the CVG genes, Fgf3 and NeuroD, were upregulated. To delineate Tbx1 cell-autonomous roles, a more selective ablation, exclusively in the OV, was performed using Pax2-Cre. In contrast to the Foxg1-Cre mutants, Pax2-Cre conditional mutant mice survived to adulthood and had normal outer and middle ears but had the same inner ear defects as the Tbx1 null mice, with the same gene expression changes. These results demonstrate that Tbx1 has non-cell autonomous roles in PPI in the formation of outer and middle ears and cell-autonomous roles in the OV. Periotic mesenchymal markers, Prx2 and Brn4 were normal in both conditional mutants, whereas they were diminished in Tbx1-/- embryos. Thus, Tbx1 in the surrounding mesenchyme in both sets of conditional mutants cannot suppress the defects in the OV that occur in the null mutants.

Animals↗
PubMed2006

Competence of cranial ectoderm to respond to Fgf signaling suggests a two-step model of otic placode induction.

Vertebrate craniofacial sensory organs derive from ectodermal placodes early in development. It has been suggested that all craniofacial placodes arise from a common ectodermal domain adjacent to the anterior neural plate, and a number of genes have been recently identified that mark such a 'pre-placodal' domain. However, the functional significance of this pre-placodal domain is still unclear. In the present study, we show that Fgf signaling is necessary and sufficient to directly induce some, but not all, markers of the otic placode in ectoderm taken from the pre-placodal domain. By contrast, ectoderm from outside this domain is not competent to express otic markers in response to Fgfs. Grafting naïve ectoderm into the pre-placodal domain causes upregulation of pre-placodal markers within 8 hours, together with the acquisition of competence to respond to Fgf signaling. This suggests a two-step model of craniofacial placode induction in which ectoderm first acquires pre-placodal region identity, and subsequently differentiates into particular craniofacial placodes under the influence of local inducing signals.

Animals↗
PubMed2006

Wnt signals mediate a fate decision between otic placode and epidermis.

The otic placode, the anlagen of the inner ear, develops from an ectodermal field characterized by expression of the transcription factor Pax2. Previous fate mapping studies suggest that these Pax2(+) cells will give rise to both otic placode tissue and epidermis, but the signals that divide the Pax2(+) field into placodal and epidermal territories are unknown. We report that Wnt signaling is normally activated in a subset of Pax2(+) cells, and that conditional inactivation of beta-catenin in these cells causes an expansion of epidermal markers at the expense of the otic placode. Conversely, conditional activation of beta-catenin in Pax2(+) cells causes an expansion of the otic placode at the expense of epidermis, and the resulting otic tissue expresses exclusively dorsal otocyst markers. Together, these results suggest that Wnt signaling acts instructively to direct Pax2(+) cells to an otic placodal, rather than an epidermal, fate and promotes dorsal cell identities in the otocyst.

Animals↗
PubMed2005

Distinct roles for hindbrain and paraxial mesoderm in the induction and patterning of the inner ear revealed by a study of vitamin-A-deficient quail.

The hindbrain and cranial paraxial mesoderm have been implicated in the induction and patterning of the inner ear, but the precise role of the two tissues in these processes is still not clear. We have addressed these questions using the vitamin-A-deficient (VAD) quail model, in which VAD embryos lack the posterior half of the hindbrain that normally lies next to the inner ear. Using a battery of molecular markers, we show that the anlagen of the inner ear, the otic placode, is induced in VAD embryos in the absence of the posterior hindbrain. By performing grafting and ablation experiments in chick embryos, we also show that cranial paraxial mesoderm which normally lies beneath the presumptive otic placode is necessary for otic placode induction and that paraxial mesoderm from other locations cannot induce the otic placode. Two members of the fibroblast growth factor family, FGF3 and FGF19, continue to be expressed in this mesodermal population in VAD embryos, and these may be responsible for otic placode induction in the absence of the posterior hindbrain. Although the posterior hindbrain is not required for otic placode induction in VAD embryos, the subsequent patterning of the inner ear is severely disrupted. Several regional markers of the inner ear, such as Pax2, EphA4, SOHo1 and Wnt3a, are incorrectly expressed in VAD otocysts, and the sensory patches and vestibulo-acoustic ganglia are either greatly reduced or absent. Exogenous application of retinoic acid prior to 30 h of development is able rescue the VAD phenotype. By performing such rescue experiments before and after 30 h of development, we show that the inner ear defects of VAD embryos correlate with the absence of the posterior hindbrain. These results show that induction and patterning of the inner ear are governed by separate developmental processes that can be experimentally uncoupled from each other.

Animals↗
PubMed2005

Dlx gene expression during chick inner ear development.

Members of the Dlx gene family play essential roles in the development of the zebrafish and mouse inner ear, but little is known regarding Dlx genes and avian inner ear development. We have examined the inner ear expression patterns of Dlx1, Dlx2, Dlx3, Dlx5, and Dlx6 during the first 7 days of chicken embryonic development. Dlx1 and Dlx2 expression was seen only in nonneuronal cells of the cochleovestibular ganglion and nerves from stage 21 to stage 32. Dlx3 marks the otic placode beginning at stage 9 and becomes limited to epithelium adjacent to the hindbrain as invagination of the placode begins. Dlx3 expression then resolves to the dorsal otocyst and gradually becomes limited to the endolymphatic sac by stage 30. Dlx5 and Dlx6 expression in the developing inner ear is first seen at stages 12 and 13, respectively, in the rim of the otic pit, before spreading throughout the dorsal otocyst. As morphogenesis proceeds, Dlx5 and Dlx6 expression is seen throughout the forming semicircular canals and endolymphatic structures. During later stages, both genes are seen to mark the distal surface of the forming canals and display expression complementary to that of BMP4 in the vestibular sensory regions. Dlx5 expression is also seen in the lagena macula and the cochlear and vestibular nerves by stage 30. These findings suggest important roles for Dlx genes in the vestibular and neural development of the avian inner ear.

Amino Acid Sequence↗
PubMed2004

In vitro growth and differentiation of mammalian sensory hair cell progenitors: a requirement for EGF and periotic mesenchyme.

The sensory hair cells and supporting cells of the organ of Corti are generated by a precise program of coordinated cell division and differentiation. Since no regeneration occurs in the mature organ of Corti, loss of hair cells leads to deafness. To investigate the molecular basis of hair cell differentiation and their lack of regeneration, we have established a dissociated cell culture system in which sensory hair cells and supporting cells can be generated from mitotic precursors. By incorporating a Math1-GFP transgene expressed exclusively in hair cells, we have used this system to characterize the conditions required for the growth and differentiation of hair cells in culture. These conditions include a requirement for epidermal growth factor, as well as the presence of periotic mesenchymal cells. Lastly, we show that early postnatal cochlear tissue also contains cells that can divide and generate new sensory hair cells in vitro.

Animals↗
PubMed2004

Expression of mouse Foxi class genes in early craniofacial development.

Recent models of craniofacial development suggest the existence of a common pan-placodal domain lying next to the neural plate, from which all sensory placodes will arise. In support of this idea, several genes are expressed in the surface ectoderm of the head adjacent to the neural plate, before the appearance of genes in specific cranial placodes. In this study, we examine the expression patterns of the mouse Foxi class genes from embryonic day 6.5 to 10.5. Foxi2 is expressed throughout the cranial ectoderm adjacent to the neural plate from the 4-somite stage, later becoming excluded from the otic placode. Foxi3 is expressed in a broad region of the pan-placodal ectoderm adjacent to the neural plate from embryonic day (E) 6.75 to the first somite stage. Its expression becomes restricted to the ectoderm and the endoderm of the branchial pouches at E10.5. Foxi1 expression is first detected in the endolymphatic duct in the otic vesicle at E10.5. These results suggest that the mouse Foxi class genes may play important roles, both during cranial placode specification and in later development of individual cranial sensory structures and other organs derived from the cranial ectoderm.

Animals↗
PubMed2004

Generation of Pax2-Cre mice by modification of a Pax2 bacterial artificial chromosome.

The Pax2 gene is expressed in the developing otocyst, kidney, and midbrain-hindbrain boundary. We generated Pax2-Cre transgenic lines by modification of a Pax2 bacterial artificial chromosome (BAC). In one Pax2-Cre line, Cre mRNA starts to be expressed in the otic placode at the late presomite stage. R26R reporter mouse analysis revealed that the Cre expression is sufficient to delete the loxP-flanked sequences in most of the cells in the inner ear. Reporter-positive cells are also detected in other Pax2-expressing tissues such as midbrain, cerebellum, olfactory bulb, and kidney, suggesting that these cells are the descendants of Pax2-expressing cells in these tissues and that Pax2-Cre transgenic mice can delete genes efficiently in these tissues.

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