E-box factors in the developing brain

The superfamily of basic helix-loop-helix (bHLH) factors is strongly involved in brain development and neural stem cell specification. A subfamily of this huge family of transcription factors are the E-box factors, consisting of Tcf3, Tcf4, and Tcf12. We have shown that both Tcf4 and Tcf12 have a crucial role in the development of different cellular systems in the brain, like the cortex, corpus callosum and hippocampus (Tcf4), and mesodiencephalic dopaminergic neurons (Tcf4 and Tcf12). 

Haplo-insufficiency of TCF4 in humans leads to Pitt-Hopkins syndrome, characterized by, amongst others, severe intellectual disability, typical facial gestalt, breathing abnormalities, and gastro-intestinal problems. By investigating the role of Tcf4 in brain development, we aim to gain more insight in the underlying molecular cascades and brain areas affected in Pitt-Hopkins syndrome patients, which is key to understanding this debilitating disease and in pinpointing possible therapeutic targets.

Our current research focuses mainly on the role of Tcf4 in (brain) development and can be divided into 4 different research lines

• Development of the medulla oblongata
• Regulation of oligodendrogenesis and brain myelination
• Mutational analysis in Pitt-Hopkins Syndrome
• Gut development and development of the enteric nervous system

Tcf4 in the development of the medulla oblongata

Pitt-Hopkins patients show severe breathing abnormalities in which they show periods of hyperventilation alternated with periods of severe hypoventilation or even complete absence of breathing. We hypothesize that one of the cuases of this problem may lie in an affected development of the medulla oblongata. This brain area is highly conserved between species and functions as a relay center in the regulation of vital cardiovascular, respiratory, and autonomic functions via highly specified medullary nuclei. The neurons that make up these nuclei originate from one (or more) of twelve specific progenitor zones in the medulla. As Tcf4 is expressed in the developing medulla oblongata, it may have a role in the correct development and functioning of these nuclei.

To gain more insight in the origin and development of the neurons in the different medullary nuclei we have mapped the development of these nuclei from progenitor to functional neuron. Based on this mapping and the expression of Tcf4 in the developing medulla we can make a proper estimation of which nuclei are dependent on Tcf4 for their development. 

Tcf4 in regulation of oligodendrogenesis and brain myelination

Defected myelination is one of the brain-specific characteristics in Pitt-Hopkins Syndrome patients. Myelination is crucial for neural functioning and communication. This proces is regulated by oligodendrocytes and continues until 21 years of age in humans. Next to this, it has been shown that mouse mutants with a Tcf4 mutation also show a defective myelin profile in the brain. We propose that Tcf4 is involved in the regulation of oligodendrogenesis and the ultimate maturation and functioning of oligodendrocytes. As oligodendrogenesis and myelination occurs relatively late during brain development and proceeds many years after birth, this would be a good starting point for a possible therapeutic target. With this research line we aim to gain more insight in the regulation of oligodendrogenesis by Tcf4 and investigate how Tcf4 regulates the generation of functioning oligodendrocytes and brain myelination.

Mutational analysis of Pitt-Hopkins Syndrome (PTHS)

Pitt-Hopkins Syndrome (PTHS) is a neurodevelopmental disorder caused by de novo mutations in the TCF4 gene. As a result, individuals with PTHS are unique with regards to the mutation they harbour and pathological symptoms. By researching the functional consequences on the protein level of these different TCF4 mutations, we aim to determine whether the location of the mutation within the TCF4 gene can help us understand the clinical outcome in PTHS

Tcf4 in gut development and development of the enteric nervous system

One of the clinical hallmarks of PTHS is gastro-intestinal (GI) abnormalities, with about 80% of the individuals with PTHS suffering from severe constipation and abdominal bloating. Together with experts from the Tytgat institute on gut development, the PTHS expertise team at the AUMC, and patient-organisations like Pitt-Hopkins UK and the Pitt-Hopkins foundation, we aim to determine the molecular and cellular mechanisms underlying these GI problems. 

BSc Psychobiology

• Celbiologie; year 1 PB; course coordinator and lecturer
• Ontwikkeling; year 2 PB; lecturer
• Experimentatie - Moleculaire Celbiologie; year 2 PB; course coordinator
• Moleculaire Neurobiologie; year 3 PB; course coordinator and lecturer
• Bachelor Project; year 3 PB; supervisor

BSc Biomedical Sciences

• Bachelor Project; year 3 BMW; supervisor

MSc Molecular Neuroscience

• Genetic cascades in development practical; year 1 MNS; course coordinator and lecturer
• Master Research Project; year 1 and 2 MNS; supervisor

Extra educational tasks

• Member of the curriculum committee
• Learning trajectory coordinator: Genetics and Molecular Celbiologie
• Part of Open-Inquiry Teaching community (SURF grant)