Dlx transcription factors regulate differentiation of dopaminergic neurons of the ventral thalamus

Recent studies have provided many lines of evidence that specific homeodomain factors act to regulate differentiation into specific neuron types. However, these studies have mainly focused on the caudal CNS, while in the forebrain, the regulation of neuron specification remains relatively unknown. To investigate the genetic regulatory networks that control neuron differentiation in the forebrain, we have analyzed the expression patterns and functions of DLX homeodomain factors in the ventral thalamus of early mouse embryos. During initial neurogenesis (E9.5-E10.5), DLX(+) cells are the first progenitors to make terminal divisions and differentiate as neurons. We have defined a set of regulatory genes coexpressed with DLX, in both progenitors (PAX6 and MASH1) and in the differentiating neurons (PAX6, along with a combination of LIM-type homeodomain factors, including ISL1, Lhx1/Lim1, and Lhx5/Lim2). These initial neurons express tyrosine hydroxylase (TH), and become the PAX6-expressing A13 dopaminergic neurons of the zona incerta. To test for DLX function, the initial differentiation of the ventral thalamic neurons was examined in embryos mutant for Dlx1 and Dlx2. Dlx1/2 double homozygous mutants formed ventral thalamic neurons, but these neurons lacked PAX6, ISL1, and TH expression. These data suggest that DLX genes act as forebrain-specific factors linking general neuron-inducing signals to region-specific neuron differentiation programs.