Dr. Hugh Bennett
Professor - Department of Medicine, Division of Experimental Medicine
Progranulin, Zebrafish, Motorneuron Development.
The zebrafish has emerged as a model organism that is expected to define the mechanisms underlying the development of functions unique to vertebrates including humans (i.e. the heart, blood vessels, and advanced nervous and immune systems). We are using the Zebrafish to study the function of a new family of tissue growth factors (the granulins) discovered in the Endocrine Laboratory. In mammals, over-expression of the single granulin gene has been shown to contribute to the progression of certain tumours including those of the breast and prostate. In contrast granulin gene under-expression resulting from the loss of one allele has been shown to lead to a form of frontotemporal dementia in human patients. We have shown that in the zebrafish, the granulins are members of a multi-gene family that are critically involved in early embryonic development. Knockdown of granulin gene expression leads to a profound disruption of organ formation including interference in normal development of the central nervous system, internal organs, blood cells and blood vessels. One of the more tractable consequences of knockdown of pgrna in Zebrafish is disruption of normal caudal motor neuron development. We are using this developmental assay to define the mechanism of action of progranulin and applying this knowledge to the development of model therapeutics with potential for treating chronic neurological diseases.
1. Role of progranulin gene expression in zebrafish motor neuron development.
2. Structure and function of zebrafish prohormone convertases.