Recent studies of mouse mutant aphakia have implicated the homeobox gene Pitx3 in the survival of substantia nigra dopaminergic neurons, the degeneration of which causes Parkinson's disease. To directly investigate a role for Pitx3 in midbrain DA neuron development, we have analysed a line of Pitx3-null mice that also carry an eGFP reporter under the control of the endogenous Pitx3 promoter. We show that the lack of Pitx3 resulted in a loss of nascent substantia nigra dopaminergic neurons at the beginning of their final differentiation. Pitx3 deficiency also caused a loss of tyrosine hydroxylase (TH) expression specifically in the substantia nigra neurons. Therefore, our study provides the first direct evidence that the aphakia allele of Pitx3 is a hypomorph and that Pitx3 is required for the regulation of TH expression in midbrain dopaminergic neurons as well as the generation and/or maintenance of these cells. Furthermore, using the targeted GFP reporter as a midbrain dopaminergic lineage marker, we have identified previously unrecognised ontogenetically distinct subpopulations of dopaminergic cells within the ventral midbrain based on their temporal and topographical expression of Pitx3 and TH. Such an expression pattern may provide the molecular basis for the specific dependence of substantia nigra DA neurons on Pitx3.

We have generated embryonic stem (ES) cells and transgenic mice with green fluorescent protein (GFP) inserted into the Pitx3 locus via homologous recombination. In the central nervous system, Pitx3-directed GFP was visualized in dopaminergic (DA) neurons in the substantia nigra and ventral tegmental area. Live primary DA neurons can be isolated by fluorescence-activated cell sorting from these transgenic mouse embryos. In culture, Pitx3-GFP is coexpressed in a proportion of ES-derived DA neurons. Furthermore, ES cell-derived Pitx3-GFP expressing DA neurons responded to neurotrophic factors and were sensitive to DA-specific neurotoxin N-4-methyl-1, 2, 3, 6-tetrahydropyridine. We anticipate that the Pitx3-GFP ES cells could be used as a powerful model system for functional identification of molecules governing mDA neuron differentiation and for preclinical research including pharmaceutical drug screening and transplantation. The Pitx3 knock-in mice, on the other hand, could be used for purifying primary neurons for molecular studies associated with the midbrain-specific DA phenotype at a level not previously feasible. These mice would also provide a useful tool to study DA fate determination from embryo- or adult-derived neural stem cells.

BACKGROUND AND OBJECTIVE: Subjective social status (SSS), a person’s sense of their (or for youth, their family’s) position in the socioeconomic hierarchy, is strongly related to health in adults but not health in adolescence. Understanding this developmental discrepancy requires first understanding the developmental trajectory of SSS. The objective of this study was to identify the number and shape of SSS trajectories as adolescents transition to adulthood and explore if trajectory membership affects health. METHODS: Using data from 7436 assessments from the Princeton School District Study, a decade-long cohort study of non-Hispanic black and white youth, latent class growth models with 3 to 7 SSS trajectories were developed. Model fit, trajectory structure, and shape were used to guide optimal model selection. Using this optimal model, the associations of trajectory membership with BMI and depressive symptoms in young adulthood were explored. RESULTS: The 5-class model was optimal. In this model, trajectories were persistent high (7.8%), mid–high (32.2%), middle (43.4%), low–lower (7.4%), and high–low (9.1%). Non-Hispanic black race/ethnicity, lower household income, and low parent education were associated with membership in this high–low trajectory. High–low trajectory membership was associated with higher BMI and depressive symptoms in non-Hispanic white subjects but was not associated with depressive symptoms. It was associated with lower BMI only after adjustment for BMI in adolescence in non-Hispanic black subjects. CONCLUSIONS: SSS is relatively stable in adolescence and the transition to adulthood, and it generally reflects objective markers of social advantage. However, socially disadvantaged youth with high SSS in early adolescence may be at increased health risk.

Background Prenatal traffic-related air pollution exposure is linked to adverse birth outcomes. However, modifying effects of maternal body mass index (BMI) and infant sex remain virtually unexplored. Objectives We examined whether associations between prenatal air pollution and birth weight differed by sex and maternal BMI in 670 urban ethnically mixed mother-child pairs. Methods Black carbon (BC) levels were estimated using a validated spatio-temporal land-use regression (LUR) model; fine particulate matter (PM2.5) was estimated using a hybrid LUR model incorporating satellite-derived Aerosol Optical Depth measures. Using stratified multivariable-adjusted regression analyses, we examined whether associations between prenatal air pollution and calculated birth weight for gestational age (BWGA) z-scores varied by sex and maternal pre-pregnancy BMI. Results Median birth weight was 3.3±0.6 kg; 33% of mothers were obese (BMI ≥30 kg/m3). In stratified analyses, the association between higher PM2.5 and lower birth weight was significant in males of obese mothers (−0.42 unit of BWGA z-score change per IQR increase in PM2.5, 95%CI: −0.79 to −0.06) ( PM2.5 × sex × obesity Pinteraction=0.02). Results were similar for BC models (Pinteraction=0.002). Conclusions Associations of prenatal exposure to traffic-related air pollution and reduced birth weight were most evident in males born to obese mothers.