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Development. January 1, 2008; 135 (2): 249-58.

Convergence of a head-field selector Otx2 and Notch signaling: a mechanism for lens specification.

Ogino H , Fisher M , Grainger RM .

Xenopus is ideal for systematic decoding of cis-regulatory networks because its evolutionary position among vertebrates allows one to combine comparative genomics with efficient transgenic technology in one system. Here, we have identified and analyzed the major enhancer of FoxE3 (Lens1), a gene essential for lens formation that is activated in the presumptive lens ectoderm (PLE) when commitment to the lens fate occurs. Deletion and mutation analyses of the enhancer based on comparison of Xenopus and mammalian sequences and in vitro and in vivo binding assays identified two essential transcriptional regulators: Otx2, a homeodomain protein expressed broadly in head ectoderm including the PLE, and Su(H), a nuclear signal transducer of Notch signaling. A Notch ligand, Delta2, is expressed in the optic vesicle adjacent to the PLE, and inhibition of its activity led to loss, or severe reduction, of FoxE3 expression followed by failure of placode formation. Ectopic activation of Notch signaling induced FoxE3 expression within head ectoderm expressing Otx2, and additional misexpression of Otx2 in trunk ectoderm extended the Notch-induced FoxE3 expression posteriorly. These data provide the first direct evidence of the involvement of Notch signaling in lens induction. The obligate integration of inputs of a field-selector (Otx2) and localized signaling (Notch) within target cis-regulatory elements might be a general mechanism of organ-field specification in vertebrates (as it is in Drosophila). This concept is also consistent with classical embryological studies of many organ systems involving a ;multiple-step induction''.

PubMed ID: 18057103
PMC ID: PMC3918164
Article link: Development.
Grant support: EY06675 NEI NIH HHS , EY10283 NEI NIH HHS , EY17400 NEI NIH HHS , RR13221 NCRR NIH HHS , R01 EY006675 NEI NIH HHS , R01 EY010283 NEI NIH HHS , R01 EY017400 NEI NIH HHS , R01 RR013221 NCRR NIH HHS , R01 EY010283 NEI NIH HHS , R01 EY006675 NEI NIH HHS , R01 EY017400 NEI NIH HHS , EY10283 NEI NIH HHS , EY17400 NEI NIH HHS , EY06675 NEI NIH HHS , R01 RR013221 NCRR NIH HHS , RR13221 NCRR NIH HHS

Genes referenced: dlc dll1 foxe3 mt4 mtnr1a notch1 notch2 otx2

Bao, 1997, Pubmed[+]

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