Bradley-Schmieg, NE; (2016) Analysis of Kidins220 alternative splice isoforms. Doctoral thesis , UCL (University College London).

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Abstract

Neurodevelopment relies on neuronal cell survival or death happening at the right time in the right place. The expression and distribution of specific growth factor receptors are crucial for neuronal fate. Neurotrophin receptors (NTRs) are a family of receptors consisting of Trk receptors and p75NTR, which regulate neurite outgrowth, cell survival and death. Kinase-D interacting Substrate of 220 kDa (Kidins220) is a transmembrane protein interacting with NTRs. It is a downstream target of tropomyosin-receptor kinase (Trk) receptors and acts as a binding partner for p75NTR. Kidins220 has a crucial function in the nervous and cardiovascular system and is necessary for life. In the framework of this thesis, I discovered the occurrence of several Kidins220 alternative splice variants and investigated their unique binding partners and potential functions. Kidins220 alternative splice isoforms are spatio-temporally expressed and can be altered by neurotrophins and synaptic activity. Depending on their C-terminal ending, Kidins220 alternative splice isoforms are located in different cellular compartments. Different Kidins220 alternative splice isoforms have specific binding partners, involved in receptor anchoring, synaptic vesicle endocytosis and recycling processes, indicating a role for Kidins220 isoforms in various cell functions. Furthermore, Kidins220 alternative splice isoforms play a role in NTR signalling and localisation, potentially influencing neurite outgrowth and differentiation in neurons. Importantly, I found that Kidins220 isoforms play a role in vivo within brain and heart development and fertility. Taken together, I demonstrate in the work reported in this thesis the existence of novel Kidins220 splice isoforms with unique properties. My work adds new complexity to the functional regulation of NTRs, and potentially to other pathways involved in neuronal and cardiovascular development. This thesis is completed by an additional chapter on “Nidogens as therapeutic targets for tetanus prevention”, a project I temporarily took over and progressed during a colleague's maternity leave.

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