Chemokines and their role in dopaminergic development

Sammanfattning: The main pathological hallmark in Parkinson s disease (PD) is the progressive loss of dopaminergic (DA) neurons in the substantia nigra (SN), affecting movements such as walking, talking and writing. Today, there is no cure available for PD and existing treatments only provide symptomatic relief, but the prospect of using stem cell based cell replacement therapies for patients with PD have provided new optimism. In order to improve the efficiency of DA neuron production, engraftment and function, a solid understanding of the molecular mechanisms that govern DA neurogenesis is crucial. In recent years, morphogens and intrinsic DA neuron determinants, that enable stem and progenitor cells to establish proper identity, have been identified. However, the whole story has yet to be uncovered. In order to improve the efficiency of DA neuron production, engraftment and function, a solid understanding of the molecular mechanisms that govern DA neurogenesis and differentiation is crucial. This thesis examines the expression and function of chemokines during DA neurogenesis. In paper I we demonstrate that three alpha-chemokines, CXCL1, -6 and -8, increase the number of DA neurons in ventral midbrain (VM) precursor and neurosphere cultures by diverse mechanisms. CXCL6 does so by promoting the differentiation of Nurr1+ precursors into DA neurons in vitro. Intriguingly, CXCL8, a ligand expressed only in homo sapiens, enhanced progenitor cell division, neurogenesis and Tyrosine hydroxylase positive (TH+) cell number in rodent precursor and neurosphere cultures. CXCL1, the murine ortholog of CXCL8, was developmentally regulated in the VM and exhibited similar, but not identical activities to CXCL8. In paper II we identify two ?-chemokines, CCL2 and CCL7, as novel regulators of DA neurogenesis. CCL2 and CCL7 were found to promote the development of DA neurons by selectively enhancing the differentiation of Nurr1+ precursors into TH+ DA neurons. Moreover, both CCL2 and CCL7 were found to increase neuritogenesis in TH+ neurons in VM precursor and neurosphere cultures. In paper III we report that CXCL12/CXCR4 signaling regulates migration of A9-A10 DA neurons, neuritogenesis and the initial orientation of their processes. Taken together, our data provides evidence that chemokines are highly involved in DA neuron development and suggest that they may be useful to enhance DA cell preparations for cell replacement therapy as well as for drug discovery in PD.