We used cortex-specific deletion of the transcription factor gene COUP-TFI (also known as Nr2f1) in mice to demonstrate previously unknown fundamental roles for it in patterning mammalian neocortex into areas. The highest COUP-TFI expression is observed in the cortical progenitors and progeny in parietal and occipital cortex that form sensory areas, and the lowest expression was observed in frontal cortex that includes motor areas. Cortical deletion of COUP-TFI resulted in massive expansion of frontal areas, including motor, to occupy most of neocortex, paralleled by marked compression of sensory areas to caudal occipital cortex. These area patterning changes are preceded and paralleled by corresponding changes in molecular markers of area identity and altered axonal projections to maintain patterned area-specific input and output connections. We conclude that COUP-TFI is required for balancing patterning of neocortex into frontal/motor and sensory areas by acting in its expression domain to repress frontal/motor area identities and to specify sensory area identities.
The neuron-specific transcription factor T-box brain 1 (TBR1) regulates brain development. Disruptive mutations in the TBR1 gene have been repeatedly identified in patients with autism spectrum disorders (ASDs). Here, we show that Tbr1 haploinsufficiency results in defective axonal projections of amygdalar neurons and the impairment of social interaction, ultrasonic vocalization, associative memory and cognitive flexibility in mice. Loss of a copy of the Tbr1 gene altered the expression of Ntng1, Cntn2 and Cdh8 and reduced both inter- and intra-amygdalar connections. These developmental defects likely impair neuronal activation upon behavioral stimulation, which is indicated by fewer c-FOS-positive neurons and lack of GRIN2B induction in Tbr1(+/-) amygdalae. We also show that upregulation of amygdalar neuronal activity by local infusion of a partial NMDA receptor agonist, d-cycloserine, ameliorates the behavioral defects of Tbr1(+/-) mice. Our study suggests that TBR1 is important in the regulation of amygdalar axonal connections and cognition.
Cerebral cortex is comprised of regions including six-layer neocortex and three-layer olfactory cortex generated by telencephalic progenitors of an Emx1 lineage. The mechanism specifying region-specific subpopulations within this lineage is unknown. We show in mouse that the LIM homeodomain transcription factor Lhx2, expressed in graded levels by progenitors, determines their regional identity and fate decisions to generate neocortex or olfactory cortex. Emx1-Cre deletion of Lhx2 at E10.5 refates progenitors to generate three-layer cortex phenocopying olfactory cortex rather than lateral neocortex. Progenitors do not generate ectopic olfactory cortex following Lhx2 deletion at E11.5. Thus, Lhx2 regulates a regional-fate decision by telencephalic progenitors during a critical period that closes as they differentiate from neuroepithelial cells to neuronogenic radial glia. “Exposure” of progenitors to Lhx2 may dictate their regional-fate decisions. These findings establish a genetic mechanism determining regional fate in the Emx1 lineage of telencephalic progenitors that generate cerebral cortex.
This review accompanies a 2016 SFN mini-symposium presenting examples of current studies that address a central question: How do neural stem cells (NSCs) divide in different ways to produce heterogeneous daughter types at the right time and in proper numbers to build a cerebral cortex with the appropriate size and structure? We will focus on four aspects of corticogenesis: cytokinesis events that follow apical mitoses of NSCs; coordinating abscission with delamination from the apical membrane; timing of neurogenesis and its indirect regulation through emergence of intermediate progenitors; and capacity of single NSCs to generate the correct number and laminar fate of cortical neurons. Defects in these mechanisms can cause microcephaly and other brain malformations, and understanding them is critical to designing diagnostic tools and preventive and corrective therapies.
A hundred years after Lhx2 ortholog apterous was identified as a critical regulator of wing development in Drosophila, LIM-HD gene family members have proved to be versatile and powerful components of the molecular machinery that executes the blueprint of embryogenesis across vertebrate and invertebrate species. Here, we focus on the spatio-temporally varied functions of LIM-homeodomain transcription factor LHX2 in the developing mouse forebrain. Right from its earliest known role in telencephalic and eye field patterning, to the control of the neuron-glia cell fate switch, and the regulation of axon pathfinding and dendritic arborization in late embryonic stages, LHX2 has been identified as a fundamental, temporally dynamic, always necessary, and often sufficient factor in a range of critical developmental phenomena. While Lhx2 mutant phenotypes have been characterized in detail in multiple brain structures, only recently have we advanced in our understanding of the molecular mechanisms by which this factor acts. Common themes emerge from how this multifunctional molecule controls a range of developmental steps in distinct forebrain structures. Examining these shared features, and noting unique aspects of LHX2 function is likely to inform our understanding of how a single factor can bring about a diversity of effects and play central and critical roles across systems and stages. The parallels in LHX2 and APTEROUS functions, and the protein complexes they participate in, offer insights into evolutionary strategies that conserve tool kits and deploy them to play new, yet familiar roles in species separated by hundreds of millions of years.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.