Functional and genetic studies in MEN2 and Hirschsprung disease

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Hirschsprung disease (HSCR) and Multiple Endocrine Neoplasia type 2 (MEN2) are two seemingly unrelated neural crest-associated disorders that can be caused by germline mutations in RET. HSCR and MEN2 have distinct characteristics and different tissues are affected in each disease. However, in both diseases the basic problem is the disruption of signal transduction pathways required for normal physiological functions. This thesis presents a functional and genetic study on HSCR and MEN2, and aimed at unravelling the protein networks involved in the development of these disorders.
Part I of this thesis focuses on HSCR, which is an inherited disorder characterized by the absence of enteric neurons in the distal part of the colon. It can occur as an isolated trait, but is frequently associated with other congenita malformations present in rare, recessive syndromes. The study of the genes involved in these syndromes can yield new insights into the HSCR-related protein network and may help identify new HSCR candidate genes. One of these rare, recessive syndromes is called Goldberg-Shprintzen syndrome, for which mutations in KBP/KIAA1279 were found to be the causal entity. In Chapter 2 the function of the protein encoded by KBP/KIAA1279, the Kinesin-Binding Protein (KBP) was studied. Since the KBP function was largely unclear, we performed expression studies in zebrafish and found that KBP is expressed in the central and enteric nervous system. In addition, we showed that KBP is involved in neuronal differentiation and neurite outgrowth. In order to determine the KBP protein network, a yeast two-hybrid screen was performed.
Several kinesin-like proteins were found to interact with KBP, as expected. KBP was also found to interact with SCG10, a microtubule-destabilizing protein. This interaction was further confirmed by co-immunoprecipitation, co-localization and by epistasis experiments in zebrafih, thus linking KBP to microtubule dynamics. Since a direct interaction between KBP and microtubules could not be found, it is likely that KBP exerts its effect via SCGlO interaction

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