Cux-1 and Cux-2 control the development of Reelin expressing cortical interneurons.

Homeodomain transcription factors play important roles in the specification and differentiation of neuronal subpopulations. In the cerebral cortex, the expression patterns of Cux-1 and Cux-2 in the medial ganglionic eminence (MGE) suggest a role for these transcription factors in the development of interneurons, a heterogeneous neuronal population. In this report, we describe expression of Cux-1 and Cux-2 proteins in Reelin-secreting interneurons of the cortical plate, but not in calretinin or parvalbumin subpopulations. The role of Cux genes in the development of Reelin positive neurons was studied using Cux-1 and Cux-2 knockout mice. These experiments demonstrate that Cux-1-/-; Cux-2-/- double mutation is embryonically lethal. Although this phenotype is highly penetrant, a small proportion of mice develop to birth (P0). Analysis of these animals demonstrate that expression of Reelin is completely absent in layers II-IV of Cux-1-/-; Cux-2-/- double mutant mice, but it is not affected in the cortex of Cux-1-/- or Cux-2-/- single mutants. No Cux-1-/-; Cux-2-/- double-mutant were collected after P0. Since, GABA-ergic populations mature at late postnatal stages, this did not allow us to analyze the expression of subclass specific markers and define the affected interneuron subpopulations. Our analysis of Cux-1-/-; Cux-2-/- double mutant thus demonstrates essential yet redundant roles for Cux-1 and Cux-2 in specifying Reelin expressing cortical interneurons.