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Role of Hes1 in Hair Cell Differentiation 4553 Reported (Zheng Et Al., 1999A)

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Role of Hes1 in Hair Cell Differentiation 4553 Reported (Zheng Et Al., 1999A) Development 127, 4551-4560 (2000) 4551 Printed in Great Britain © The Company of Biologists Limited 2000 DEV4430 Hes1 is a negative regulator of inner ear hair cell differentiation J. Lisa Zheng1, Jianyong Shou2, Francois Guillemot3, Ryoichiro Kageyama4 and Wei-Qiang Gao1* 1Department of Neuroscience, Genentech, Inc., South San Francisco, CA 94080, USA 2Molecular Oncoclogy, Genentech, Inc., South San Francisco, CA 94080, USA 3Institut de Genetique et de, Biologie Moleculaire et Cellulaire, 67404 Illkirch, C.U. de Strasbourg, France 4Institute for Virus Research, Kyoto University, Shogoin-Kawahara, Sakyo-ku, Kyoto 606-8507, Japan *Author for correspondence (e-mail: [email protected]) Accepted 15 August; published on WWW 9 October 2000 SUMMARY Hair cell fate determination in the inner ear has been sensory epithelium. In the cochlea, Hes1 is selectively shown to be controlled by specific genes. Recent loss- expressed in the greater epithelial ridge and lesser of-function and gain-of-function experiments have epithelial ridge regions which are adjacent to inner and demonstrated that Math1, a mouse homolog of the outer hair cells. Co-transfection experiments in postnatal Drosophila gene atonal, is essential for the production of rat explant cultures show that overexpression of Hes1 hair cells. To identify genes that may interact with Math1 prevents hair cell differentiation induced by Math1. and inhibit hair cell differentiation, we have focused on Therefore Hes1 can negatively regulate hair cell Hes1, a mammalian hairy and enhancer of split homolog, differentiation by antagonizing Math1. These results which is a negative regulator of neurogenesis. We report suggest that a balance between Math1 and negative here that targeted deletion of Hes1 leads to formation of regulators such as Hes1 is crucial for the production of an supernumerary hair cells in the cochlea and utricle of the appropriate number of inner ear hair cells. inner ear. RT-PCR analysis shows that Hes1 is expressed in inner ear during hair cell differentiation and its expression is maintained in adulthood. In situ hybridization with late Key words: Cell fate determination, Notch signaling, bHLH embryonic inner ear tissue reveals that Hes1 is expressed transcription factor, Hes, Math1, Cochlea, Utricle, Hair cell in supporting cells, but not hair cells, of the vestibular development, Hair cell regeneration INTRODUCTION cochlea are probably derived from the greater epithelial ridge (GER) and the lesser epithelial ridge (LER) cells, respectively, The bony labyrinth of the inner ear develops from the otic during embryogenesis (see Lim and Rueda, 1992). vesicle (Van de Water, 1983; Fekete, 1996) and consists of the Hair cell differentiation in the inner ear is likely to be cochlea and vestibular end organs including the utricle, saccule controlled by specific genes (for recent reviews see Fekete, and three semicircular canals. Each of these structures contains 1996, 1999). So far one of the most crucial genes for the a sensory epithelium in which hair cells, mechanosensory cells, control of inner ear hair cell differentiation appears to be the which convert sound or motion signals into electrochemical mouse basic helix-loop-helix (bHLH) transcription factor energy, and supporting cells are located. Currently, little is Math1 (Atoh1 – Mouse Genome Informatics), a mammalian known about the signaling events underlying inner ear homolog of Drosophila atonal. Math1 has been shown to be a development, specifically, differentiation of hair cells. positive regulator for the differentiation of cerebellar granule Classical tritiated thymidine incorporation studies have shown neurons (Ben-Arie et al., 1997), dorsal commissural that hair cells become postmitotic between E11.5 and E17.5, interneurons (Helms and Johnson, 1998) and inner ear hair with a peak at E13.5 in rodents (Ruben, 1967; Sans and Chat, cells (Bermingham et al., 1999; Zheng and Gao, 2000). 1982). Hair cells in the mammalian vestibular end organs Targeted deletion of the Math1 gene leads to a failure of hair appear to be derived from the progenitor cells or supporting cell differentiation (Bermingham et al., 1999). Overexpression cells located within the sensory epithelium (Forge et al., 1993; of Math1 in postnatal rat cochlear explant cultures induces Warchol et al., 1993; Li and Forge, 1997; Zheng and Gao, production of extra hair cells in the GER (Zheng and Gao, 1997; Kuntz and Oesterle, 1998) in a similar manner as shown 2000). in birds and lower vertebrates (Corwin and Cotanche, 1988; A few other bHLH transcription factors can influence cell Ryals and Rubel, 1988; Balak et al., 1990; Fekete et al., 1998). fate determination by acting as negative regulators (Kageyama However, the exact origin of mammalian cochlear hair cells is and Nakanishi, 1997). To identify a bHLH transcription factor still unclear because no cell lineage studies using lineage that may interact with Math1 to inhibit hair cell differentiation, tracers have been performed. Previous histological studies we turned our interest to Hes1, a mammalian hairy and suggest that the inner and outer hair cells in the mammalian enhancer of split homolog, which is a negative regulator of 4552 J. L. Zheng and others neurogenesis (Ishibashi et al., 1995; Nakamura et al., 2000). graded ethanol, and dried using Hexamethyldisilazane (HMDS). The Targeted disruption of the Hes1 gene results in a precocious samples were mounted on scanning electron microscopy stubs using neuronal differentiation in the brain (Ishibashi et al., 1995) and carbon double sticky tabs (Ted Pella, Redding, CA), sputter coated in the retina (Tomita et al., 1996). The Hes1 null mutant mice with 10 nm gold-palladium (Hummer XP, Anatech, Alexandria, VA) display severe neural tube defects and die before or and viewed in a Philips SEM 525M at an accelerating voltage of 10 immediately after birth (Ishibashi et al., 1995). More recently, kV. Digital images were captured using Semicaps Genie version 1.22 software. data collected from Hes1 and Hes5 double null mutant mice has shown that Hes1 and Hes5 act together as Notch effectors Plasmid DNA construction, cochlear explant cultures, for the control of mammalian neuronal differentiation (Ohtsuka electroporation and immunocytochemistry et al., 1999). The pRK5-Math1-EGFP plasmid was constructed as previously To determine whether Hes1 influences inner ear hair cell described (Zheng and Gao, 2000), by inserting the EcoRI Math1 differentiation, we examined the inner ear phenotypes of Hes1- fragment spliced from the pCMV-Math1 plasmid (Akazawa et al., deficient mice. We found supernumerary hair cells in the 1995) into the multiple cloning site of pRK5-EGFP plasmid (Murone cochlea and in the utricle, a vestibular end organ, of the Hes1- et al., 1999). The pSV2CMV-Hes1 plasmid (Akazawa et al., 1995) ′ deficient mice. In addition, to find out the spatiotemporal contains the Ssp1(171)-EcoRI (the 3 end) fragment of rat Hes1 expression patterns of Hes1 in the inner ear, we performed RNA cDNA. Middle turn cochlear explants (with the stria vascularis removed) were dissected from P0-P1 rats as previously described in situ hybridization and RT-PCR analysis. We discovered that (Zheng and Gao, 1996, 2000). The cultures were transfected with the Hes1 was expressed in the inner ear during hair cell pRK5-Math1-EGFP plasmid, a mixture of pSV2CMV-Hes1 and differentiation period and its expression became elevated pRK5-EGFP plasmids at a ratio of 5:1 or a mixture of equal amount around birth and persisted into adulthood. Within the vestibular of pSV2CMV-Hes1 and pRK5-Math1-EGFP plasmids using an sensory epithelium, Hes1 was expressed in supporting cells, but electroporator (Model CUY-21, BEX, Tokyo) with a train of eight not hair cells. In the cochlea, Hes1 was selectively expressed in pulses: 25 V, 50 mseconds duration and 100 mseconds interval. The GER and LER regions, which are adjacent to inner and outer tissue was placed in a groove freshly made of 1% agarose gel, hair cells, respectively. Moreover, we performed co-transfection containing 3 mg/ml plasmid DNA. The top surface of the explants was positioned to face to the cathode. After electroporation, the experiments with plasmids expressing Hes1 and Math1 and µ obtained evidence that Hes1 can block the induction of ectopic explants were plated on a collagen-coated (80 g/ml rat tail collagen I in 0.02 N HCl) eight-well LabTek slide in serum-free medium as hair cells in the presence of Math1. This study suggests that described (Zheng and Gao, 1999). The cultures were then fixed at 7 Hes1 is involved in hair cell differentiation as a negative days after transfection and processed for double immunocytochemistry regulator possibly by antagonizing Math1. with anti-myosin VIIa and anti-EGFP (Chemicon) antibodies, mediated by Texas Red- and FITC-conjugated secondary antibodies as described (Zheng and Gao, 1997, 2000). MATERIALS AND METHODS Cell counts and statistical analysis Hes1 mutant mice, histology and immunostaining of the To count total myosin VIIa-positive cells from the serial cryostat inner ear tissue utricular sections, we used an ocular grid in a Zeiss Axiophot Hes1 gene disruption and genotyping of the mice were performed as microscope with 20× and 40× lenses as previously described (Zheng previously reported (Ishibashi et al., 1995). The inner ear phenotypes et al., 1999b). Phalloidin-positive and myosin VIIa-positive cells were were compared between Hes1−/− embryos and their Hes1+/− and counted from cochlear surface preparations dissected from E17.5 Hes1+/+ littermates. Cochlear explants were prepared from E17.5 Hes1−/−, Hes1+/− and Hes1+/+ mice, essentially in the same way as mice (a close time point to birth, as Hes1−/− mice die at birth) and previously described (Zheng and Gao, 1996, 1999). At E17.5, the fixed in 4% paraformaldehyde in 0.1 M phosphate buffer (pH 7.4) cochlea has formed only two turns, the basal and apical turns, and hair before they were processed with FITC-conjugated phalloidin (Zheng cells in the apical turn are not yet well-developed.
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