Molecular Marker Differences Relate to Developmental Position and Subsets of Mesodiencephalic Dopaminergic Neurons

Abstract

The development of mesodiencephalic dopaminergic (mdDA) neurons located in the substantia nigra compacta (SNc) and ventral tegmental area (VTA) follow a number of stages marked by distinct events. After preparation of the region by signals that provide induction and patterning, several transcription factors have been identified, which are involved in specifying the neuronal fate of these cells. The specific vulnerability of SNc neurons is thought to root in these specific developmental programs. The present study examines the positions of young postmitotic mdDA neurons to relate developmental position to mdDA subset specific markers. MdDA neurons were mapped relative to the neuromeric domains (prosomeres 1-3 (P1-3), midbrain, and hindbrain) as well as the longitudinal subdivisions (floor plate, basal plate, alar plate), as proposed by the prosomeric model. We found that postmitotic mdDA neurons are located mainly in the floorplate domain and very few in slightly more lateral domains. Moreover, mdDA neurons are present along a large proportion of the anterior/posterior axis extending from the midbrain to P3 in the diencephalon. The specific positions relate to some extent to the presence of specific subset markers as Ahd2. In the adult stage more of such subsets specific expressed genes are present and may represent a molecular map defining molecularly distinct groups of mdDA neurons.

Defining Midbrain Dopaminergic Neuron Diversity by Single-Cell Gene Expression Profiling

“…Heterogeneous expression of markers in the DA system has been reported (Di Salvio et al, 2010b; Dougalis et al, 2012; Fu et al, 2011; Gerfen et al, 1987; Hnasko et al, 2012; McCaffery and Dräger, 1994; Smits et al, 2013). Previous studies have relied on in situ hybridization, or antibody co-labeling with Th, to localize marker expression.…”

“…FP progenitors already display some heterogeneity, in terms of gene expression and proclivity to contribute to distinct nuclei (Blaess et al, 2011; Hayes et al, 2011; Joksimovic et al, 2009; Wallén et al, 1999). Immature DA neurons migrate from the ventricular zone into the mantle, and express a series of transcription factors and other genes, some of which are heterogeneously expressed in the nascent DA cohort (Ang, 2006; Chung et al, 2010; Di Salvio et al, 2010a; Smidt and Burbach, 2007; Smits et al, 2013). Thus, the earliest aspects of DA neuron heterogeneity appear to be established in the early embryo, although it is likely that subsequent maturation events build on, or refine, DA heterogeneity.…”

A novel floor plate boundary defined by adjacentEn1andDbx1microdomains distinguishes midbrain dopamine and hypothalamic neurons

“…One possibility is that the mdFP is subdivided along the A-P axis into lineage-restricted microdomains. Such a possibility is indeed depicted in prosomere-based models of the segmentally divided embryonic CNS (Björklund and Dunnett, 2007;Puelles and Rubenstein, 2015;Rubenstein et al, 1994;Smidt and Burbach, 2007;Smits et al, 2006Smits et al, , 2013, but evidence for such microdomains within the Shh + /Foxa2 + /Lmx1a + mdFP is limited. These models of the subdivided mdFP are based on prosomeric gene expression patterns in more dorsal CNS structures, and these genes are often not expressed in the mdFP.…”

Mapping dopaminergic deficiencies in the substantia nigra/ventral tegmental area in schizophrenia

“…The substantia nigra/ventral tegmental area (SN/VTA) complex is a heterogeneous collection of dopaminergic cell groups that extends from diencephalic to mesencephalic territories in many vertebrates, including rodents, non-human primates, and humans (Puelles and Verney 1998; see as reviews Smits et al 2006; Smidt and Burbach 2007; Smits et al 2013). The SN/VTA contains the largest number of dopaminergic neurons in the brain (see as reviews van Domburg and ten Donkelaar 1991; Haber and Fudge 1997; Nieuwenhuys et al 2008), with average estimates ranging in most studies from approximately 250,000–440,000 dopaminergic neurons within the complex (Bogerts et al 1983; Hirsch et al 1988; van Domburg and ten Donkelaar 1991; Damier et al 1999a; Kubis et al 2000).…”