Shared mechanisms causing Mowat-Wilson syndrome and Pitt-Hopkins syndrome: analysis of Sip1 and Tcf4 function in brain development, from patient to mouse to patient.

During brain development enormous numbers of neurons are born in the embryo, which have to position themselves correctly and form functional connections with each other. However, mutations or environmental factors can affect the assembly of this network and cause neurodevelopmental disorders, such as autism and syndromes like Tourettes, Mowat-Wilson (MWS) and Pitt-Hopkins (PTHS). MWS and PTHS patients have many symptoms in common such as epilepsy, intellectual disability, a much smaller head circumference, delayed psychomotor development involving sitting, walking and speech, which suggests they have a common underlying mechanism or a functional relation. This is striking as the two syndromes are caused by mutations in two different genes, SIP1 and TCF4, respectively. SIP1 and TCF4 proteins can interact with each other and co-operate in the brain, providing a possible explanation for the resemblance of the two syndromes. In this project I want to investigate the relevance of this interaction in the context of the developing brain via a unique strategy combining genetically modified mice for Sip1 and Tcf4. I will focus on the development of interneurons, cells that when dysfunctional, cause epilepsy both in mice and humans. My goal is to find why and how Sip1 and Tcf4, and possibly their co-operativity, are so important for the proper development of our brains and to provide an explanation for the brain-related features of the MWS and PTHS patients.

Keywords:Assembly of neural circuits, Cerebral cortex, Interneuron, Migration

Disciplines:Laboratory medicine, Palliative care and end-of-life care, Regenerative medicine, Other basic sciences, Other health sciences, Nursing, Other paramedical sciences, Other translational sciences, Other medical and health sciences