Hosted by the School of Biochemistry

ABSTRACT: My research is centred on the control of fate transition and cell behaviour by signalling, in particular, the molecular mechanisms regulating non-canonical Notch ligands. By elucidating the mechanisms governing the development of the central nervous system, pivotal knowledge can be added to the understanding of cell fate decisions, both in homeostasis and tumorigenesis. While extensive research has been conducted on canonical Notch ligands, regulation by vertebrate-specific non-canonical Notch ligands is not understood; however, there is increasing evidence that these ligands play a crucial role in the regulation of Notch signalling, particularly in the nervous system. We identify Delta like non-canonical Notch ligand 2/EGFL9 (Dlk2) as a regulator of zebrafish neurogenesis, with mutants exhibiting early increase and subsequent depletion of neural stem cells, decreased radial glial cells density and impaired neuronal cell distribution. This work led to uncover the direct interaction of Dlk2 with the intracellular Notch antagonist, Numb, which plays a pivotal role in neurogenesis and is a known tumour suppressor gene. The data show that Dlk2 is a gatekeeper of Numb‘s activity by preventing its aberrant phosphorylation. In addition, patients with tumours exhibiting reduced levels of Dlk2 have a poorer prognosis, suggesting potential therapeutic implications. This study highlights the importance of non-canonical Notch ligands as modulators of neurogenesis and their relevance in tumour progression. Building from these findings, my future research plans focus on bringing a mechanistic understanding of the proteome interactome network of the non-canonical Notch ligands in neural development and how the disruption of these interactions contributes to tumorigenesis in different types of pediatric and adult gliomas.