Dennis D. M. O'LEary

Significance: The mammalian neocortex is divided into specialized modality-specific areas that are responsible for the processing of sensory information. This architecture is critical, because altered area size affects normal sensory function and behavior in animals and humans. Current knowledge suggests that sensory area specification is dominated by patterning genes expressed in cortical progenitors. We show that postmitotic deletion of the transcription factor LIM homeobox 2 ( Lhx2 ) in cortical neurons does not affect area patterning in progenitors but strongly alters sensory areas, demonstrating that specification of area identity in progenitors alone is insufficient. We suggest a novel and more comprehensive model of cortical area patterning that incorporates these revelations and define the relevance of postmitotic mechanisms in determining the functional properties of cortical areas.

Primary somatosensory cortex (S1) contains a map of the body that mirrors maps in hindbrain and thalamus. During development, peripheral changes alter the map in S1. Here the authors use a mouse mutation that alters S1 size and leads to plasticity in the S1 map that is transferred to the thalamic map. The primary somatosensory cortex (S1) contains a complete body map that mirrors the subcortical maps developed by peripheral sensory input projecting to the sensory hindbrain, the thalamus and then S1. Peripheral changes during development alter these maps through 'bottom-up' plasticity. Unknown is how S1 size influences map organization and whether an altered S1 map feeds back to affect subcortical maps. We show that the size of S1 in mice is significantly reduced by cortex-specific deletion of Pax6, resulting in a reduced body map and loss of body representations by an exclusion of later-differentiating sensory thalamocortical input. An initially normal sensory thalamus was repatterned to match the aberrant S1 map by apoptotic deletion of thalamic neurons representing body parts with axons excluded from S1. Deleted representations were rescued by altering competition between thalamocortical axons using sensory deprivation or increasing the size of S1. Thus, S1 size determined the resolution and completeness of body maps and engaged 'top-down' plasticity that repatterned the sensory thalamus to match S1.

Dividing the Brain: The cerebral cortex of the brain is organized into primary cortical areas, which receive direct inputs from the thalamus, and higher-order cortical areas, which in turn receive inputs from one or more primary cortical areas. Chou et al. (p. 1239 ) investigated the mechanisms underlying the specification of higher-order cortical areas. Input from the dorsal lateral geniculate nucleus into the primary visual area (V1) is required to drive the genetic and functional differentiation of a large visual cortical field into primary and higher-order visual areas. Thalamocortical axon input acts on a large visual cortical field. The afferents from the dorsal lateral geniculate are necessary to further refine the cortex into subareas that distinguish V1 from higher processing areas. In the relatively simple model that emerges from these findings, sensory input is essential to distinguish primary and higher-order cortical areas.

Approximately one in five neurons is GABAergic in many neocortical areas and species, forming a critical balance between inhibition and excitation in adult circuits. During development, cortical GABAergic neurons are generated in ventral telencephalon and migrate up to developing cortex where the excitatory glutamatergic neurons are born. We ask here: when during development is the adult GABAergic/glutamatergic neuron ratio first established? To answer this question, we have determined the fraction of all neocortical GABAergic neurons that will become inhibitory (GAD67⁺) in mice from embryonic day 10.5 (E10.5) to postnatal day 28 (P28). We find that this fraction is close to 1/5, the adult value, starting from early in corticogenesis (E14.5, when GAD67⁺neurons are still migrating tangentially to the cortex) and continuing at the same 1/5 value throughout the remainder of brain development. Thus our data indicate the one-in-five fraction of GABAergic neurons is already established during their neuronal migration and well before significant synapse formation.

Background: The dorsal thalamus acts as a gateway and modulator for information going to and from the cerebral cortex. This activity requires the formation of reciprocal topographic axon connections between thalamus and cortex. The axons grow along a complex multistep pathway, making sharp turns, crossing expression boundaries, and encountering intermediate targets. However, the cellular and molecular components mediating these steps remain poorly understood. Results: To further elucidate the development of the thalamocortical system, we first created a thalamocortical axon reporter line to use as a genetic tool for sensitive analysis of mutant mouse phenotypes. The TCA-tau-lacZ reporter mouse shows specific, robust, and reproducible labeling of thalamocortical axons (TCAs), but not the overlapping corticothalamic axons, during development. Moreover, it readily reveals TCA pathfinding abnormalities in known cortical mutants such as reeler. Next, we performed an unbiased screen for genes involved in thalamocortical development using random mutagenesis with the TCA reporter. Six independent mutant lines show aberrant TCA phenotypes at different steps of the pathway. These include ventral misrouting, overfasciculation, stalling at the corticostriatal boundary, and invasion of ectopic cortical cell clusters. An outcross breeding strategy coupled with a genomic panel of single nucleotide polymorphisms facilitated genetic mapping with small numbers of mutant mice. We mapped a ventral misrouting mutant to the Emx2 gene, and discovered that some TCAs extend to the olfactory bulbs in this mutant. Mapping data suggest that other lines carry mutations in genes not previously known for roles in thalamocortical development. Conclusions: These data demonstrate the feasibility of a forward genetic approach to understanding mammalian brain morphogenesis and wiring. A robust axonal reporter enabled sensitive analysis of a specific axon tract inside the mouse brain, identifying mutant phenotypes at multiple steps of the pathway, and revealing a new aspect of the Emx2 mutant. The phenotypes highlight vulnerable choice points and latent tendencies of TCAs, and will lead to a refined understanding of the elements and interactions required to form the thalamocortical system. See Commentary: http://www.biomedcentral.com/1741-7007/9/1

Topographic maps are a two-dimensional representation of one neural structure within another and serve as the main strategy to organize sensory information. The retina’s projection via axons of retinal ganglion cells to midbrain visual centers, the optic tectum/superior colliculus, is the leading model to elucidate mechanisms of topographic map formation. Each axis of the retina is mapped independently using different mechanisms and sets of axon guidance molecules expressed in gradients to achieve the goal of representing a point in the retina onto a point within the target. An axon’s termination along the temporal-nasal mapping axis is determined by opposing gradients of EphAs and ephrin-As that act through their forward and reverse signaling, respectively, within the projecting axons, each of which inhibits interstitial branching, cooperating with a branch-promoting activity, to generate topographic specific branching along the shaft of the parent axons that overshoot their correct termination zone along the anterior-posterior axis of the target. The dorsal-ventral termination position is then determined using a gradient of ephrin-B that can act as a repellent or attractant depending on the ephrin-B concentration relative to EphB levels on the interstitial branches to guide them along the medial-lateral axis of the target to their correct termination zone, where they arborize. In both cases, axon-axon competition results in axon mapping based on relative rather than absolute levels of repellent or attractant activity. The map is subsequently refined through large-scale pruning driven in large part by patterned retinal activity.

The authors show that the LIM homeodomain transcription factor Lhx2 is responsible for the fate decision of cortical progenitors to generate neocortex or olfactory cortex. Conditional deletion of Lhx2 in telencephalic progenitors refated them to generate three-layer cortex resembling olfactory cortex, rather than lateral neocortex. 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 in this lineage is unknown. We found that the LIM homeodomain transcription factor Lhx2 in mice, expressed in graded levels by progenitors, determines their regional identity and fate decisions to generate neocortex or olfactory cortex. Deletion of Lhx2 with Emx1-cre at embryonic day 10.5 (E10.5) altered the fates of progenitors, causing them to generate three-layer cortex, phenocopying olfactory cortex rather than lateral neocortex. Progenitors did 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 ends as they differentiate from neuroepithelial cells to neuronogenic radial glia. These findings establish a genetic mechanism for determining regional-fate in the Emx1 lineage of telencephalic progenitors that generate cerebral cortex.