Abstract
Midbrain dopaminergic (DA) axons make long longitudinal projections towards the striatum. Despite the importance of DA striatal innervation, processes involved in establishment of DA axonal connectivity remain largely unknown. Here we demonstrate a striatal-specific requirement of transcriptional regulator Nolz1 in establishing DA circuitry formation. DA projections are misguided and fail to innervate the striatum in both constitutive and striatal-specific Nolz1 mutant embryos. The lack of striatal Nolz1 expression results in nigral to pallidal lineage conversion of striatal projection neuron subtypes. This lineage switch alters the composition of secreted factors influencing DA axonal tract formation and renders the striatum non-permissive for dopaminergic and other forebrain tracts. Furthermore, transcriptomic analysis of wild-type and Nolz1−/− mutant striatal tissue led to the identification of several secreted factors that underlie the observed guidance defects and proteins that promote DA axonal outgrowth. Together, our data demonstrate the involvement of the striatum in orchestrating dopaminergic circuitry formation.
Highlights
Midbrain dopaminergic (DA) axons make long longitudinal projections towards the striatum
We demonstrate that the striatonigral to -pallidal switch in projection neuron subtype identity in Nolz1−/− mutant embryos is associated with defects in establishment of DA and forebrain axonal tracts
Analysis of NOLZ1 expression in relation to DA axons labelled by GlycoDAT and tyrosine hydroxylase (TH) shows that NOLZ1 is expressed in regions that display the guidance phenotype e.g. the hypothalamus and striatum[19,20,21]
Summary
Midbrain dopaminergic (DA) axons make long longitudinal projections towards the striatum. We demonstrate a striatal-specific requirement of transcriptional regulator Nolz[1] in establishing DA circuitry formation. The lack of striatal Nolz[1] expression results in nigral to pallidal lineage conversion of striatal projection neuron subtypes This lineage switch alters the composition of secreted factors influencing DA axonal tract formation and renders the striatum non-permissive for dopaminergic and other forebrain tracts. After exiting the midbrain DA axons are attracted by and fasciculated within the medial forebrain bundle (MFB)[5], which forms two rostrally oriented ipsilateral tracts within the ventral diencephalon These axonal tracts run parallel to the ventral midline towards target areas in the forebrain including the striatum and cortex[6]. We demonstrate that the striatonigral to -pallidal switch in projection neuron subtype identity in Nolz1−/− mutant embryos is associated with defects in establishment of DA and forebrain axonal tracts. The acquired insight into mechanisms involved in DA circuitry formation will facilitate the development of approaches to improve graft outcome in cell transplantation studies
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