Progranulin and zebrafish motor neuron development

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BACKGROUND: The single human progranulin gene encodes a growth factor bearing multiple granulin domains that is up-regulated in many cancers relative to normal tissues. Autosomal dominant mutations within the progranulin gene have been shown to cause an early onset form of frontotemporal dementia. Recently progranulin has been shown to be a neurotrophic factor and to regulate neurite outgrowth and enhance neuronal survival. RATIONALE FOR STUDY: Despite the increasing appreciation of the biological properties of progranulin, we do not have a full understanding of its physiological functions and mode of action; in particular a membrane receptor, co-receptor or soluble binding protein has yet to be fully defined. Outlined in this proposal is a program to use the zebrafish to characterize the manner in which progranulin mediates its actions by: 1) dissecting the mechanism underlying its neurotrophic properties using antisense morpholino gene knockdown technology and 2) identifying candidate receptors and/or binding proteins by screening tissue extracts for proteins that interact with progranulin with high affinity and specificity. PRELIMINARY RESULTS: We have shown that progranulin is highly expressed in motor neurons within the mouse spinal cord and cultures of mouse embryonic spinal cord neurons. Over-expression of progranulin in the NSC-34 neuronal cell line stimulates the appearance of dendritic structures and imparts the ability to survive autonomously for very long periods in culture. Analysing the development and fate of zebrafish primary motor neurons has revealed that knockdown of progranulin-A expression leads to premature termination and inappropriate branching of developing axons. A putative soluble binding protein for progranulin, a member of the C-type lectin family was identified. FUTURE STUDIES: We will define the mechanism underlying the neurotrophic actions of progranulin. We will determine the role that proteins that interact with progranulin play in mediating its biological activities.