Ikaros promotes early-born neuronal fates in the cerebral cortex

Abstract

During cerebral cortex development, a series of projection neuron types is generated in a fixed temporal order. In Drosophila neuroblasts, the transcription factor hunchback encodes first-born identity within neural lineages. One of its mammalian homologs, Ikaros, was recently reported to play an equivalent role in retinal progenitor cells, raising the question as to whether Ikaros/Hunchback proteins could be general factors regulating the development of early-born fates throughout the nervous system. Ikaros is also expressed in progenitor cells of the mouse cerebral cortex, and this expression is highest during the early stages of neurogenesis and thereafter decreases over time. Transgenic mice with sustained Ikaros expression in cortical progenitor cells and neurons have developmental defects, including displaced progenitor cells within the cortical plate, increased early neural differentiation, and disrupted cortical lamination. Sustained Ikaros expression results in a prolonged period of generation of deep layer neurons into the stages when, normally, only late-born upper layer neurons are generated, as well as a delayed production of late-born neurons. Consequently, more early-born and fewer late-born neurons are present in the cortex of these mice at birth. This phenotype was observed in all parts of the cortex, including those with minimal structural defects, demonstrating that it is not secondary to abnormalities in cortical morphogenesis. These data suggest that Ikaros plays a similar role in regulating early temporal fates in the mammalian cerebral cortex as Ikaros/Hunchback proteins do in the Drosophila nerve cord.

Neurog2 and Ascl1 together regulate a postmitotic derepression circuit to govern laminar fate specification in the murine neocortex

“…Thus Tbr1 is expressed ectopically in both Neurog2;Ascl1 and Neurog2-Tg animals, and, accordingly, Foxg1, which is required to repress Tbr1 (17), is down-regulated. Conversely, the expression of Ikaros, which promotes an early identity (18), is upregulated in both loss-and gain-of-function models.…”

“…8E). Conversely, expression of Ikaros, the overexpression of which promotes an early deep-layer identity (18), was elevated 1.23-fold in E12.5 Neurog2…”

“…The subsequent switch from deep-to upper-layer cell fates also involves the repression of Tbr1 by Foxg1 (17). In addition, Ikaros/Ikzf1, a homolog of the temporal regulator hunchback in Drosophila, confers an early identity when overexpressed in the cortex (18). Finally, loss of Ezh2, part of polycomb repressive complex 2 (PRC2), confers an early identity to cortical progenitors (19).…”

The making of a lymphocyte: the choice among disparate cell fates and the IKAROS enigma

“…IKAROS is expressed in neuro-epithelial progenitors of the developing striatum, cortical and retinal progenitors, and the developing pituitary (Georgopoulos et al 1992;Ezzat et al 2006;Agoston et al 2007;MartinIbanez et al 2010;Alsio et al 2013). In addition to neuroepithelial cells, HELIOS is also expressed in epidermal keratinocytes (Kelley et al 1998).…”

“…HUNCHBACK maintains competence of neural progenitor cells and contributes to specification of early born neuronal cell fates (Isshiki et al 2001;Novotny et al 2002), much as IKAROS acts at multiple stages of immune cell development. IKAROS also regulates progenitor competence and early born cell fates in the mammalian nervous system (Elliott et al 2008;Tran et al 2010;Alsio et al 2013). Like IKAROS, HUNCHBACK uses the N-terminal zinc fingers to bind DNA and its C-terminal zinc fingers to dimerize (McCarty et al 2003).…”