Hey2 functions in parallel with Hes1 and Hes5 for mammalian auditory sensory organ development

<p>Abstract</p> <p>Background</p> <p>During mouse development, the precursor cells that give rise to the auditory sensory organ, the organ of Corti, are specified prior to embryonic day 14.5 (E14.5). Subsequently, the sensory domain is patterned precisely into one row of inner and three rows of outer sensory hair cells interdigitated with supporting cells. Both the restriction of the sensory domain and the patterning of the sensory mosaic of the organ of Corti involve Notch-mediated lateral inhibition and cellular rearrangement characteristic of convergent extension. This study explores the expression and function of a putative Notch target gene.</p> <p>Results</p> <p>We report that a putative Notch target gene, hairy-related basic helix-loop-helix (bHLH) transcriptional factor Hey2, is expressed in the cochlear epithelium prior to terminal differentiation. Its expression is subsequently restricted to supporting cells, overlapping with the expression domains of two known Notch target genes, <it>Hairy </it>and enhancer of split homolog genes <it>Hes1 </it>and <it>Hes5</it>. In combination with the loss of <it>Hes1 </it>or <it>Hes5</it>, genetic inactivation of <it>Hey2 </it>leads to increased numbers of mis-patterned inner or outer hair cells, respectively. Surprisingly, the ectopic hair cells in <it>Hey2 </it>mutants are accompanied by ectopic supporting cells. Furthermore, <it>Hey2</it>^-/-<it>;Hes1</it>^-/-and <it>Hey2</it>^-/-<it>;Hes1</it>^+/-mutants show a complete penetrance of early embryonic lethality.</p> <p>Conclusion</p> <p>Our results indicate that <it>Hey2 </it>functions in parallel with <it>Hes1 </it>and <it>Hes5 </it>in patterning the organ of Corti, and interacts genetically with <it>Hes1 </it>for early embryonic development and survival. Our data implicates expansion of the progenitor pool and/or the boundaries of the developing sensory organ to account for patterning defects observed in <it>Hey2 </it>mutants.</p

Dishevelled genes mediate a conserved mammalian PCP pathway to regulate convergent extension during neurulation

The planar cell polarity (PCP) pathway is conserved throughout evolution, but it mediates distinct developmental processes. In Drosophila, members of the PCP pathway localize in a polarized fashion to specify the cellular polarity within the plane of the epithelium, perpendicular to the apicobasal axis of the cell. In Xenopus and zebrafish, several homologs of the components of the fly PCP pathway control convergent extension. We have shown previously that mammalian PCP homologs regulate both cell polarity and polarized extension in the cochlea in the mouse. Here we show, using mice with null mutations in two mammalian Dishevelled homologs, Dvl1 and Dvl2, that during neurulation a homologous mammalian PCP pathway regulates concomitant lengthening and narrowing of the neural plate, a morphogenetic process defined as convergent extension. Dvl2 genetically interacts with Loop-tail, a point mutation in the mammalian PCP gene Vangl2, during neurulation. By generating Dvl2 BAC (bacterial artificial chromosome) transgenes and introducing different domain deletions and a point mutation identical to the dsh1 allele in fly, we further demonstrated a high degree of conservation between Dvl function in mammalian convergent extension and the PCP pathway in fly. In the neuroepithelium of neurulating embryos, Dvl2 shows DEP domain-dependent membrane localization, a pre-requisite for its involvement in convergent extension. Intriguing, the Loop-tail mutation that disrupts both convergent extension in the neuroepithelium and PCP in the cochlea does not disrupt Dvl2 membrane distribution in the neuroepithelium, in contrast to its drastic effect on Dvl2 localization in the cochlea. These results are discussed in light of recent models on PCP and convergent extension

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For (,), (,,), (), (), (), and (). Arrowheads in -indicate the domain for sensory and neuronal lineages in the otocyst; the bracket in marks the expression domain of ; brackets in -indicate the primordial organ of Corti at E14.5. (-) Cochlear sections from an E14.5 embryo were probed for Hes6 (), Isl1 (), and Hey2 (). Brackets indicate the developing sensory organ that was determined by careful comparison of adjacent sections with molecular markers for the region. The sides of the cochlear duct toward the center and the periphery of the spiraled cochlea are designated as the medial and lateral sides, respectively, and are indicated. Scale bars: 10 μm for -, -, -, -.<p><b>Copyright information:</b></p><p>Taken from "Hey2 functions in parallel with Hes1 and Hes5 for mammalian auditory sensory organ development"</p><p>http://www.biomedcentral.com/1471-213X/8/20</p><p>BMC Developmental Biology 2008;8():20-20.</p><p>Published online 26 Feb 2008</p><p>PMCID:PMC2277407.</p><p></p

Hey2 functions in parallel with Hes1 and Hes5 for mammalian auditory sensory organ development-6

For (,), (,,), (), (), (), and (). Arrowheads in -indicate the domain for sensory and neuronal lineages in the otocyst; the bracket in marks the expression domain of ; brackets in -indicate the primordial organ of Corti at E14.5. (-) Cochlear sections from an E14.5 embryo were probed for Hes6 (), Isl1 (), and Hey2 (). Brackets indicate the developing sensory organ that was determined by careful comparison of adjacent sections with molecular markers for the region. The sides of the cochlear duct toward the center and the periphery of the spiraled cochlea are designated as the medial and lateral sides, respectively, and are indicated. Scale bars: 10 μm for -, -, -, -.<p><b>Copyright information:</b></p><p>Taken from "Hey2 functions in parallel with Hes1 and Hes5 for mammalian auditory sensory organ development"</p><p>http://www.biomedcentral.com/1471-213X/8/20</p><p>BMC Developmental Biology 2008;8():20-20.</p><p>Published online 26 Feb 2008</p><p>PMCID:PMC2277407.</p><p></p

Hey2 functions in parallel with Hes1 and Hes5 for mammalian auditory sensory organ development-3

Lated from animals with the genotypes specified (). The percent of the number of hair cells in extra rows was calculated against the number of normally patterned hair cells in the same cochlea, and plotted for each genotype specified in the graph (). The distribution of mis-patterned hair cells along the longitudinal axis of the cochlea was indicated (). Note the uniform increase of ectopic hair cells along the longitudinal axis of the cochlea in and mutants. The p values for statistic significance among the groups in each bracket are indicated (,).<p><b>Copyright information:</b></p><p>Taken from "Hey2 functions in parallel with Hes1 and Hes5 for mammalian auditory sensory organ development"</p><p>http://www.biomedcentral.com/1471-213X/8/20</p><p>BMC Developmental Biology 2008;8():20-20.</p><p>Published online 26 Feb 2008</p><p>PMCID:PMC2277407.</p><p></p

Hey2 functions in parallel with Hes1 and Hes5 for mammalian auditory sensory organ development-5

Ies against p27/Kip1 (,), BrdU (), or doubly stained for Myosin6 and BrdU (-). Brackets in (-) indicate the primordial organ of Corti at E14.5 that is marked by the expression of p27/Kip1. Note that BrdUproliferating cells are at the region medial to the developing organ of Corti at this stage. Brackets and arrowhead (-indicate the outer and inner hair cells, respectively. Note that no BrdUcells were detected in the organ of Corti following BrdU injections and a chasing period. Scale bar: 10 μm.<p><b>Copyright information:</b></p><p>Taken from "Hey2 functions in parallel with Hes1 and Hes5 for mammalian auditory sensory organ development"</p><p>http://www.biomedcentral.com/1471-213X/8/20</p><p>BMC Developmental Biology 2008;8():20-20.</p><p>Published online 26 Feb 2008</p><p>PMCID:PMC2277407.</p><p></p

Hey2 functions in parallel with Hes1 and Hes5 for mammalian auditory sensory organ development-2

E18.5, and stained for a hair cell marker, Myosin6. Images from the apical (, , , ), middle (,,,), and basal (,,,) regions of the cochlea along the longitudinal axis were included. Arrowheads indicate the region that separates the inner from outer hair cells. Extra rows of outer hair cells (,,-indicated by brackets) and inner hair cell doublet (indicated by asterisks) were seen in mutant samples in comparison to the wild-type control (-). Scale bar: 10 μm.<p><b>Copyright information:</b></p><p>Taken from "Hey2 functions in parallel with Hes1 and Hes5 for mammalian auditory sensory organ development"</p><p>http://www.biomedcentral.com/1471-213X/8/20</p><p>BMC Developmental Biology 2008;8():20-20.</p><p>Published online 26 Feb 2008</p><p>PMCID:PMC2277407.</p><p></p

Hey2 functions in parallel with Hes1 and Hes5 for mammalian auditory sensory organ development-1

() or (). The inner (arrows in -) and outer hair cell regions (brackets in -) are indicated. The arrows in -indicate the layer of supporting cells. () The dynamic expression of in the developing cochlea is schematically diagramed. At E14.5, the expression domain of (grey lines) overlaps with that of (green lines) and p27/Kip1 (black) at its medial and lateral borders, respectively. At E16.5, is expressed similarly to that of (red lines) and (yellow lines) in a subset of supporting cells, while p27/Kip1 is present in all the cells surrounding hair cells (open circles). By E17.5, the expression of has started to be down-regulated from the organ of Corti at the basal region where the expression of remains. Scale bar: 10 μm for -.<p><b>Copyright information:</b></p><p>Taken from "Hey2 functions in parallel with Hes1 and Hes5 for mammalian auditory sensory organ development"</p><p>http://www.biomedcentral.com/1471-213X/8/20</p><p>BMC Developmental Biology 2008;8():20-20.</p><p>Published online 26 Feb 2008</p><p>PMCID:PMC2277407.</p><p></p