Lineage Analysis of Cxcr4-Expressing Cells in the Developing Midbrain Suggests That Progressive Competence Restriction in Dopaminergic Progenitor Cells Contributes to the Establishment of Dopaminergic Neuronal Diversity

Abstract

Midbrain dopaminergic (mDA) neurons are generated from a ventral midbrain progenitor zone over a time span of several days [embryonic day 10.0 (E10.0) to E14.5 in mouse]. Within this neurogenic period, a progressively changing fate potential of mDA progenitors could contribute to the generation of diverse mDA neuronal subpopulations. To test this idea, we combined inducible genetic fate mapping and intersectional labeling approaches to trace the lineage of cells expressing the chemokine receptor CXCR4. The Cxcr4 transcript is expressed in mDA progenitors and precursors, but not in differentiated mDA neurons. Cxcr4-expressing mDA progenitors/precursors labeled at E11.5 develop into a broad range of mDA neurons, whereas labeling of the Cxcr4 lineage at later time points (E12.5-E15.5) results in an increasingly restricted contribution to mDA neurons proceeding from lateral to medial in the substantia nigra and from dorsal to ventral in the ventral tegmental area. In parallel, the innervation of dopaminergic projection targets by mDA neurons derived from Cxcr4-expressing cells is becoming more restricted: the late-generated mDA neurons innervate only the medial-rostral regions in the dorsal striatum and only the medial shell in the nucleus accumbens. Our results suggest that mDA progenitor cells become increasingly restricted in their cell fate potential over time.

Keywords: development; dopaminergic diversity; intersectional genetic labeling; lineage tracing; midbrain; mouse.