The crux of Cux genes in neuronal function and plasticity

•Cut/Cux/CDP family of proteins belongs to the CUT class of homeobox genes.•Cux genes are expressed during neurogenesis and in specific neuronal subpopulations.•Perturbation of Cux expression is implicated in various diseases.•Expression of Cux1/2 in the cortex is restricted to neurons of the upper layers.•Cux1 and Cux2 TF are potential targets for plasticity and reprogramming. Cux1 and Cux2 are the vertebrate members of a family of homeodomain transcription factors (TF) containing Cut repeat DNA-binding sequences. Perturbation of their expression has been implicated in a wide variety of diseases and disorders, ranging from cancer to autism spectrum disorder (ASD). Within the nervous system, both genes are expressed during neurogenesis and in specific neuronal subpopulations. Their role during development and circuit specification is discussed here, with a particular focus on the cortex where their restricted expression in pyramidal neurons of the upper layers appears to be responsible for many of the specialized functions of these cells, and where their functions have been extensively investigated. Finally, we discuss how Cux TF represent a promising avenue for manipulating neuronal function and for reprogramming.