A key aim of neurodevelopmental research is to understand how precursor cells decide to stop dividing and commence their terminal differentiation at the correct time and place. Here, we show that minibrain (mnb), the Drosophila ortholog of the Down syndrome candidate gene DYRK1A, is transiently expressed in newborn neuronal precursors known as ganglion cells (GCs). Mnb promotes the cell cycle exit of GCs through a dual mechanism that regulates the expression of the cyclin-dependent kinase inhibitor Dacapo, the homolog of vertebrate p27Kip1 (Cdkn1b). Mnb upregulates the expression of the proneural transcription factor (TF) Asense, which promotes Dacapo expression. Mnb also induces the expression of Prospero, a homeodomain TF that in turn inhibits the expression of Deadpan, a pan-neural TF that represses dacapo. In addition to its effects on Asense and Prospero, Mnb also promotes the expression of the neuronal-specific RNA regulator Elav, strongly suggesting that Mnb facilitates neuronal differentiation. These actions of Mnb ensure the precise timing of neuronal birth, coupling the mechanisms that regulate neurogenesis, cell cycle control and terminal differentiation of neurons.
The authors declare no competing or financial interests.
M.N.S., F.G.-A., J. Ceron, J. Colonques and B.H. performed experiments and analyzed the data. F.J.T. developed the concepts, performed experiments, analyzed the data and wrote the manuscript.
This work was supported by grants from the Dirección General de Investigación Científica y Técnica [BFU2009-08831, BFU2012-38892 to F.J.T.]; the Generalitat Valenciana [ACOMP/2012/047 to F.J.T.]; and the Fundación Inocente Inocente [050666100002 to F.J.T.]. J. Ceron and J. Colonques were recipients of PhD fellowships from the Ministerio de Educación y Ciencia. M.N.S. was recipient of a Santiago Grisolia Fellowship from the Generalitat Valenciana.
Supplementary information available online at http://dev.biologists.org/lookup/doi/10.1242/dev.134338.supplemental
- Received December 18, 2015.
- Accepted July 25, 2016.