-Chemokines Regulate Proliferation, Neurogenesis And Dopaminergic Differentiation Of Ventral Midbrain Precursors And Neurospheres

¹ Laboratory of Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Karolinska Institute, Scheeles väg 1, 17177 Stockholm, Sweden.
² Laboratory of Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Karolinska Institute, Scheeles väg 1, 17177 Stockholm, Sweden.; Departamento de Biología Celular y Molecular, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile.

^* To whom correspondence should be addressed. E-mail: Ernest.Arenas{at}ki.se.

	Abstract

Increasing evidence suggests that -chemokines serve several important functions in the nervous system including regulation of neuroimmune responses, neurotransmission, neuronal survival and CNS development. In this study, we first examined the function of two -chemokines, CXCL6 and CXCL8, and their receptors, CXCR1 and CXCR2, in the developing rat ventral midbrain (VM). We found that CXCR2 and CXCL6 are regulated during VM development and that CXCL6 promotes the differentiation of Nurr1+ precursors into dopaminergic (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. TH+ cells derived from chemokine-treated VM neurospheres co-expressed Nurr1 and VMAT, and were functionally active, as shown by calcium (Ca²⁺) fluxes in response to AMPA. In conclusion, our data demonstrates that CXCL1, 6 and 8 increase the number of DA neurons in VM precursor and neurosphere cultures by diverse mechanisms. Thus, -chemokines may find an application in the preparation of cells for drug development or Parkinson's disease cell replacement therapy.