Hashimoto, K.; (2008) The role of notch signaling in mid-hindbrain boundary formation and maintenance. Doctoral thesis , University of London.

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Abstract

During embryonic development, organiser centres form at compartment boundaries and provide a source of graded signals that instruct cells to specific identities in a concentration-dependent manner. The mid-hindbrain boundary (Geling et al., 2004) is an organiser that arises in the developing neural tube at the interface between midbrain and hindbrain, and is crucial for the formation of tectum and cerebellum. Local organisers at boundaries have been best studied in invertebrates (Ahmed et al., 2003) where the Notch signalling pathway is important. Recent studies suggest that this signalling cascade may also control boundary and organiser formation in vertebrates. In this thesis I have tested the hypothesis that Notch signalling is important during MHB development. I have found that genes involved in the Notch signalling pathway are specifically expressed in domains within the chick neural tube that demarcate the MHB from early somite stages, implicating Notch signalling in the establishment of this organiser. I examined the effect on cells of experimentally altering Notch activity levels. Activation of the Notch pathway regulates cell affinity properties, as cells containing activated Notch are excluded from rhombomeres 1 and 2.1 tested the hypothesis that LFng acts as a switch to activate Notch only on the midbrain side of the boundary. Perturbation of LFng expression leads to disruption of the boundary and cell lineage restriction is lost. Ectopic activation of the Notch signalling pathway perturbs expression of key MHB organiser genes, FgfS and Wntl. In contrast, in the absence of Notch signalling, the MHB fails to form properly. I propose that Notch signalling through the ligand Serrate! is sufficient for the generation of boundaries in this region of the CNS. Together, these data suggest a role for Notch signalling both in the formation of the MHB, and also in the regulation of cell affinity differences necessary to stabilise and maintain the organiser.

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