PhD defence J.C. (Judith) Birkhoff

Extensive work using conditional knockout (cKO) mouse models in various systems, including in the central and peripheral nervous systems (CNS, PNS), and varying from embryonic
to early-postnatal or adult mouse studies, have identified the multi-domain zinc-finger transcription factor Zeb2 as critical regulator of cell fate and maturation. An updated review on
Zeb2 is presented first. In the cell nucleus Zeb2 acts as a negative regulator of differentiationinhibitory growth factor signalling. For example, in vivo functional analyses have demonstrated that Zeb2 is crucial for eliciting the necessary anti-BMP and anti-Wnt activities in myelinogenesis in the embryonic CNS (brain, spinal cord). In addition, also anti-Notch and anti-Sox2 activities in myelination and re-myelination by adult Schwann cells in the PNS haven been demonstrated. Cultured pluripotent mouse embryonic stem cells (ESCs) wherein Zeb2 is not detectably expressed, upregulate Zeb2 gene transcription when submitted to differentiation. This is necessary for the downregulation of core pluripotency genes and of Cdh1 to co-promote epithelial-to-mesenchymal transition (EMT). Both processes are compromised in Zeb2-KO mouse ESCs which stall in an epiblast stem-cell like state and cannot exit from primed pluripotency. They thus show impaired differentiation to neuroectodermal cell types, but also fail to enter general differentiation. In humans, haplo-insufficiency of ZEB2 causes Mowat-Wilson syndrome (MOWS, OMIM #235730), a monogenic, rare syndrome associated with intellectual disability, epilepsy, Hirschsprung disease (as result of ZEB2 deficiency in the neural crest lineage), and multiple other congenital anomalies. This PhD research represents a significant step forward to further develop and use cellular models for functional studies of Zeb2 and of MOWS. Moreover, within this thesis mouse ESCs and human induced pluripotent cells (iPSCs) are used in various omics experiments 
to study the regulation of Zeb2 at gene and protein level, and its action mechanisms during healthy and MOWS neural differentiation.

The PhD defences will not take place publicly in the usual way. A live stream link has been provided to candidate. The ceremony will begin exactly at 10:30.