Lhx2 Selector Activity Specifies Cortical Identity and Suppresses Hippocampal Organizer Fate

Abstract

The earliest step in creating the cerebral cortex is the specification of neuroepithelium to a cortical fate. Using mouse genetic mosaics and timed inactivations, we demonstrated that Lhx2 acts as a classic selector gene and essential intrinsic determinant of cortical identity. Lhx2 selector activity is restricted to an early critical period when stem cells comprise the cortical neuroepithelium, where it acts cell-autonomously to specify cortical identity and suppress alternative fates in a spatially dependent manner. Laterally, Lhx2 null cells adopt antihem identity, whereas medially they become cortical hem cells, which can induce and organize ectopic hippocampal fields. In addition to providing functional evidence for Lhx2 selector activity, these findings show that the cortical hem is a hippocampal organizer.

Modeling human cortical development in vitro using induced pluripotent stem cells

“…We demonstrate that the hiPSC-derived radial glia express, like human radial glia, GFAP; the intermediate progenitors express TBR2, and the neurons express MAP2 and a variety of TFs specifying cortical neuron identities. The multilayered structures at day 50 in vitro expressed the four TFs (LHX2, FOXG1, PAX6, and EMX2) that are fundamentally required for the formation of the six-layered dorsal pallium by suppressing dorsomedial and ventral telencephalic fates (30)(31)(32). These 3D structures also express many other TFs (FEZF2, BRN2, TBR1, CTIP2, and CUX1) and extracellular signaling molecules (RELN and EFNB2) known to direct cortical layer formation and identities.…”

“…For example, upper-layer neurons in the human cortex outnumber those of lower layers, whereas in our 3D structures at day 50 the proportions of lower-layer neurons were higher than those of upper layers, likely owing to the early stage of our preparation. Indeed, at day 50 in vitro the 3D structures displayed a gene expression profile typical of the dorsal telencephalon at an early stage, including FOXG1, which controls the specification of the neocortex from archicortex (33,34), LHX2, which specifies the dorsal pallium as distinct from the cortical hem (31), and GLI3, which specifies dorsal from ventral telencephalon (35). Other highly expressed TFs reflect the acquisition of rostral (frontal) cortical area identities [i.e., PAX6 (32,36)], which agrees with the high correlation found between gene expression in our 3D structures and the human frontal cortical primordium (see below).…”

Regulatory logic of neuronal diversity: Terminal selector genes and selector motifs

“…Do neuronal terminal selector gene exist in more complex nervous systems as well? The selector gene concept has already been applied to TFs acting in neuronal specification in flies and vertebrates (24,(26)(27)(28)(29)), yet it is not known whether in those cases the respective TF is truly a terminal selector gene that directly acts on terminal differentiation gene batteries. Terminal differentiation gene batteries that define individual neuron types are beginning to be identified in vertebrates by using transcriptome analysis from isolated cells (30).…”

Developmental Expression Pattern of Hspb8 mRNA in the Mouse Brain: Analysis Through Online Databases

“…We interpreted and annotated the aforementioned image series from late postnatal, adult and aging stages following the neuroanatomical description and nomenclature of Franklin and Paxinos (2008), while the analysis of the embryonic brain was made principally according to Foster (1998) and some works dealing with the development of specific structures (i.e., Fujita et al, 1966;Altman and Bayer, 1990;Yamada et al, 2000;Mangale et al, 2008;Li et al, 2009). We also took advantage of the Allen Reference Atlas (http://mouse.…”