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Region-specific endodermal signals direct neural crest cells to form the three middle ear ossicles
Ankamreddy, Harinarayana,Min, Hyehyun,Kim, Jae Yoon,Yang, Xiao,Cho, Eui-Sic,Kim, Un-Kyung,Bok, Jinwoong The Company of Biologists Limited 2019 Development (Cambridge) Vol.146 No.2
<P>Defects in the middle ear ossicles – malleus, incus and stapes – can lead to conductive hearing loss. During development, neural crest cells (NCCs) migrate from the dorsal hindbrain to specific locations in pharyngeal arch (PA) 1 and 2, to form the malleus-incus and stapes, respectively. It is unclear how migratory NCCs reach their proper destination in the PA and initiate mesenchymal condensation to form specific ossicles. We show that secreted molecules sonic hedgehog (SHH) and bone morphogenetic protein 4 (BMP4) emanating from the pharyngeal endoderm are important in instructing region-specific NCC condensation to form malleus-incus and stapes, respectively, in mouse. Tissue-specific knockout of <I>Shh</I> in the pharyngeal endoderm or <I>Smo</I> (a transducer of SHH signaling) in NCCs causes the loss of malleus-incus condensation in PA1 but only affects the maintenance of stapes condensation in PA2. By contrast, knockout of <I>Bmp4</I> in the pharyngeal endoderm or <I>Smad4</I> (a transducer of TGFβ/BMP signaling) in the NCCs disrupts NCC migration into the stapes region in PA2, affecting stapes formation. These results indicate that region-specific endodermal signals direct formation of specific middle ear ossicles.</P><P><B>Summary:</B> Tissue-specific mouse knockouts reveal specific roles for endodermal SHH and BMP4 signals in development of the malleus-incus in pharyngeal arch 1 and the stapes in pharyngeal arch 2, respectively.</P>
Shin, Jeong-Oh,Ankamreddy, Harinarayana,Jakka, Naga Mahesh,Lee, Seokwon,Kim, Un-Kyung,Bok, Jinwoong UPV/EHU Press 2017 The international journal of developmental biology Vol.61 No.8
<P>The mammalian inner ear is a complex organ responsible for balance and hearing. Sonic hedgehog (Shh), a member of the Hedgehog (Hh) family of secreted proteins, has been shown to play important roles in several aspects of inner ear development, including dorsoventral axial specification, cochlear elongation, tonotopic patterning, and hair cell differentiation. Hh proteins initiate a downstream signaling cascade by binding to the Patched 1 (Ptch1) receptor. Recent studies have revealed that other types of co-receptors can also mediate Hh signaling, including growth arrest-specific 1 (Gas1), cell-adhesion molecules-related/down-regulated by oncogenes (Cdon), and biregional Cdon binding protein (Boc). However, little is known about the role of these Hh co-receptors in inner ear development. In this study, we examined the expression patterns of Gas1, Cdon, and Boc, as well as that of Ptch1, in the developing mouse inner ear from otocyst (embryonic day (E) 9.5) until birth and in the developing middle ear at E15.5. Ptch1, a readout of Hh signaling, was expressed in a graded pattern in response to Shh signaling throughout development. Expression patterns of Gas1, Cdon, and Boc differed from that of Ptch1, and each Hh co-receptor was expressed in specific cells and domains in the developing inner and middle ear. These unique and differential expression patterns of Hh co-receptors suggest their roles in mediating various time-and space-specific functions of Shh during ear development.</P>