Research objectives
Zebrafish brain development and homeostasis
Our laboratory is interested in how vertebrate central nervous system (CNS) develops and how homeostasis of the adult brain is maintained. As a model we study zebrafish.
Current projects
Forward genetics to study brain development
To identify genes that are involved in early CNS development we carried out a 500 genomes mutagenesis screen using at the tailbud stage as a “readout” expression of neural plate regional marker genes emx1, axial, and wnt1 and at 24 hours post fertilization islet1 that labels certain primary neurons. In collaboration with Corinne Houart (MRC Centre for Developmental Neurobiology, London) we have identified and are studying axon guidance defects in a number of mutants. Based on phenotypes 30 mutants were chosen for further characterization and half of them were assigned to linkage groups. Currently we are analyzing and positionally cloning a number of these mutants. Student projects: positional cloning of the mutants with molecular biology, genomics and bioinformatics integrated.
Wnt signalling in brain development and neurogenesis
Wnt signaling is crucial for different aspects of CNS development. we generated a number of Wnt-pathway mutants to study how Wnt pathway directs (1) neural plate patterning i.e. establishment of antero-to-posterior polarity, (2) how it determines cell fate depending on the context ranging from promoting neural stem cell proliferation to directing differentiation of sensory linage (3) and most recently how it functions in axon guidance. Student projects entail phenotypic and functional analysis of single and compound Wnt-pathway mutants with emphasis on neural precursor fate.
Zebrafish as a model for Alzheimer's Disease
Missense mutations in presenilins (PS) are the major cause of familial Alzheimer's disease (FAD). In the Alzheimer's disease research field there is an important discussion whether the increased production of amyloid ß-peptide (Aß 42 ) in FAD reflects a gain-of-function (GOF) or a partial loss-of-function (LOF) of these PS mutations. Since PS mediate endoproteolysis of Notch yet another important question is whether disturbances of Notch signaling may contribute to FAD and if so, whether this occurs in a Aß-independent fashion. This is highly relevant as some FAD therapeutics being currently developed act through inhibition of presenilin/ gamma-secretase thereby also inhibiting the Notch pathway. If FAD-PS mutations appear to be LOF of PS then Notch signaling could already be impaired and its further inhibition by drugs that block PS could accelerate rather than attenuate the progress of the disease. Using target-selected gene inactivation as well as transgenic approaches we are generating an allelic series of mutations in zebrafish PS that are homologous to PS mutations from FAD patients as well as full null alleles. Neuropathology and Notch signalling will be analyzed in these mutants. We envisage that this strategy will reveal whether aberrancies in Notch due to PS mutations may contribute to neuropathology of FAD and establish usefulness of zebrafish as an AD model. Student projects: phenotypic and functional analysis of neuropathology of adult brain in presenilin mutants.
Ankyrin and SOCS box genes in establishment of precursor cell compartment
We are interested in a family of Ankyrin repeat and the Suppressor of Cytokine Signaling (SOCS) proteins (ASBs) since our current data support a hypothesis that a subfamily of ASB genes is implicated in an expansion of the progenitor cell pool. Proteins that contain a SOCS box can bring their binding partners to the ubiquitination machinery, containing elongin B/C, cullin5 and Rbx1, ultimately leading to their ubiquitination. Little is known about physiological function of ASBs. To study their function we are generating loss-of-function mutants using target-selected gene inactivation. Student projects: Asb11 function in Notch pathway.
About the group leader
Publication list
