Research

There are two main research interests in the Ekker laboratory as outlined below: 1) Function and Regulation of Dlx homeobox genes during vertebrate forebrain development; and 2) Zebrafish as a model for the study of Parkinson’s disease.

Function and Regulation of Dlx homeobox genes during vertebrate forebrain development:
Dlx homeobox genes play a crucial role in the differentiation and migration of GABAergic interneuron precursors. The Dlx genes of vertebrates are organized in bigene clusters with a short intergenic region in which we have identified cis-regulatory elements (CREs) with forebrain activity. Our analysis of Dlx CREs in the mousehas provided evidence for distinct sub-populations of GABAergic interneuron precursors in the mouse forebrain. We are currently characterizing the phenotype of mice with targeted mutations in Dlx CREs. We have also generated lines of transgenic zebrafish expressing the Cre recombinase under the control of dlx CREs in order to perform lineage tracing studies for GABAergic interneurons during brain development and in the regenerating CNS of adult zebrafish. Finally, we are using chromosome conformation capture (3C) to examine the physically interactions between Dlx Cre and the gene promoters. This study is of particular interest to address the functional significance of the bigene cluster arrangement of Dlx genes in vertebrates. Our work will provide important information on the function of Dlx genes in GABAergic interneurons, whose impaired development has been associated with conditions such as epilepsy, schizophrenia and autism.

Zebrafish as a model for the study of Parkinson’s disease:
We are using transgenic approaches to examine mechanisms of dopaminergic (DA) neuron development, loss and regeneration. We have previously generated transgenic zebrafish that express GFP in dopaminergic neurons using regulatory elements of the dopamine transporter (dat) gene. A similar line of fish has been produced in which mCherry is targeted specifically to mitochondria of DA neurons in order to follow, in real time mitochondria dynamics upon stress or altered gene activity. To specifically ablate DA neurons in adult zebrafish and examine the mechanisms responsible for their regeneration, we have generated a line of transgenic zebrafish that express the nitroreductase enzyme in DA neurons. Treatments of these transgenic animals with the pro-drug metronidazole result in DA neuron death. In parallel to this work, we are conducting functional and regulation studies of zebrafish genes (pink1, parkin, parl and synuclein) associated with early-onset Parkinson’s disease. For example, elucidation of regulatory mechanisms responsible for up-regulation of parkin will be useful in screens for drugs that lead to enhanced parkin expression and possible neuroprotection. The aforementioned transgenic zebrafish models also contribute to the PD gene studies.