Postmitotic regulation of sensory area patterning in the mammalian neocortex by Lhx2

Abstract

Current knowledge suggests that cortical sensory area identity is controlled by transcription factors (TFs) that specify area features in progenitor cells and subsequently their progeny in a one-step process. However, how neurons acquire and maintain these features is unclear. We have used conditional inactivation restricted to postmitotic cortical neurons in mice to investigate the role of the TF LIM homeobox 2 (Lhx2) in this process and report that in conditional mutant cortices area patterning is normal in progenitors but strongly affected in cortical plate (CP) neurons. We show that Lhx2 controls neocortical area patterning by regulating downstream genetic and epigenetic regulators that drive the acquisition of molecular properties in CP neurons. Our results question a strict hierarchy in which progenitors dominate area identity, suggesting a novel and more comprehensive two-step model of area patterning: In progenitors, patterning TFs prespecify sensory area blueprints. Sequentially, sustained function of alignment TFs, including Lhx2, is essential to maintain and to translate the blueprints into functional sensory area properties in cortical neurons postmitotically. Our results reemphasize critical roles for Lhx2 that acts as one of the terminal selector genes in controlling principal properties of neurons.terminal selector genes | epigenetic mechanisms | neuronal fate | MeCP2 | CoupTF1T he adult mammalian cortex is patterned into distinct and modality-specific sensory areas that are responsible for the perception of the sensory information and for the control of behavior (1). Research has focused in particular on how transcription factors (TFs), which are expressed in gradients in the cortical ventricular zone (VZ) progenitors, drive area patterning of mature cortical sensory areas by specifying their size and position during early cortical development (1, 2). As a result, current views suggest that the specification of sensory area identity is dominated by patterning events in progenitors (1-3). However, the mechanisms that translate area-patterning information from cortical progenitors into area-specific properties of postmitotic (CP) neurons are not well understood. ResultsWe hypothesized that sensory area identity in CP neurons in mice could be determined ultimately by the function of key regulators that function postmitotically. One of the few TFs that are expressed in progenitors and neurons is LIM-homeodomain 2 (Lhx2) (4). During early corticogenesis, Lhx2 shows a caudal/ medial-high to rostral/lateral-low expression gradient in cortical progenitors. Starting from around embryonic day (E) 12 to postnatal day (P) 0, a caudal/lateral-high to rostral/medial-low expression gradient is apparent in cortical neurons (Fig. S1), which postnatally becomes restricted to more uniform expression in upper cortical layers (Fig. S1). Such sustained and dynamic expression of Lhx2 in neurons suggests that Lhx2, similarly to its established roles exerted in progenitors (4-8), may affect properties in cortical neurons...

Generation and analysis of an improved Foxg1-IRES-Cre driver mouse line

“…6A). Finally, when area patterning was examined using Serotonin (5-HT) immunostaining on tangential sections of the flattened cortex, which reveals terminations of thalamocortical axons in cortical layer 4 of the corresponding primary sensory areas (Fujimiya et al, 1986; Zembrzycki et al, 2015a), we found no differences in overall cortical or area sizes and their patterning between wild type and Foxg1-IRES-Cre heterozygous mice (Fig. 6B).…”

Aberrant transcriptomes and DNA methylomes define pathways that drive pathogenesis and loss of brain laterality/asymmetry in schizophrenia and bipolar disorder

“…A recent study combining serial analysis of gene expression and transcription factor binding site prediction identified 64 novel candidate target genes of NR2E1 involved in neocortical development (Schmouth et al, 2015). These include LHX2, which is involved in "post-mitotic regulation of sensory area patterning in the mammalian neocortex" (Zembrzycki, Perez-Garcia, Wang, Chou, & O'Leary, 2015) and its cofactor SOX9. It is also known that coordination and cooperation between NR2E1 and PAX6 is required for brain patterning during development (Stenman, Yu, Evans, & Campbell, 2003).…”

LHX2 Interacts with the NuRD Complex and Regulates Cortical Neuron Subtype DeterminantsFezf2andSox11

“…Therefore, an obvious question is whether the effects of LHX2 removal are relevant in the ventricular zone progenitors themselves, or in the newly postmitotic neurons they produce. A recent study that used NexCre to delete LHX2 specifically in postmitotic neurons starting from E11 offers clarity on this issue (Zembrzycki et al, 2015). This study elegantly demonstrated that NexCre action is not seen in proliferating progenitors in the ventricular zone but is seen in newly postmitotic cells (Zembrzycki et al, 2015, their Figure S2) and that molecular specification of the different cortical layers is not affected (Zembrzycki et al, 2015, their Fig.…”