Cyclin D1 Again Caught in the Act: Dyrk1a Links G1 and Neurogenesis in Down Syndrome

Down syndrome (DS) was first described in 1866 by John Langdon the developing brain, they observed decreased nuclear levels of cyclin Down and it is now recognized as themost common chromosomal disorder and cause of intellectual disability (Haydar and Reeves, 2012). Despite its prevalence (roughly 1 in 1000 births), the cause of the disease was not identified until 1959 when karyotyping enabled the identification of trisomy 21 as responsible for the majority of DS cases (Haydar and Reeves, 2012). The complete sequence of chromosome 21 was determined in the year 2000 (Hattori et al., 2000). Yet, as researchers have discovered time and again, knowledge of an organism's genetic sequence does not necessarily translate into a precise understanding of molecular and cellular processes. Almost sixty years have passed since the cause of the disease was identified; yet the mechanisms underlying DS remain obscure. In this issue of EBioMedicine, Najas et al. expandour knowledge of DS by showing that the dosage of the evolutionarily conserved tyrosine kinase Dyrk1a, encoded by a gene located on chromosome 21 and triplicated in DS, alters the cell cycle, and hence the fate, of neural stem cells (Najas et al., 2015-in this issue). During mammalian corticogenesis, radial glial (RG) cells primarily divide to either expand their own population or produce intermediate progenitors (IPs). IPs have limited proliferative potential and predominantly generate neurons (Taverna et al., 2014). Interestingly, both the regulation of the switch of RG cells from expansion to generation of IPs as well as the proliferative potential of IPs are intimately linked to cell cycle length (Borrell and Calegari, 2014). Specifically, the G1 phase is known to lengthen as neurogenesis progresses and overexpression of cell cycle regulators such as cyclin D1 shortens G1 and promotes proliferative (at the expense of neurogenic) divisions (Borrell and Calegari, 2014). Changes in cell cycle regulation and cell fate change of neural progenitors were already reported in trisomic mouse models of DS (Haydar and Reeves, 2012) and it was also known that Dyrk1a could somehow influence both cell cycle progression and neurogenesis in vitro and in vivo (Soppa et al., 2014; Yabut et al., 2010). However, these previous studies could not assess the dose-dependent effect of Dyrk1a and quantify its effects on specific phases of the cell cycle. To address this, Najas and colleagues generated a number of mouse lines in which either three or one allele of Dyrk1a was present. Focusing on