Cajal-Retzius (CR) cells of the developing neocortex secrete Reelin (Reln), a glycoprotein involved in neuronal migration. CR cells selectively express p73, a p53 family member implicated in cell survival and apoptosis. Immunocytochemistry in prenatal human telencephalon reveals a complex sequence of migration waves of p73- and Reln-immunoreactive (IR) neurons into the cortical marginal zone (MZ). At early preplate stages, p73/Reln-IR cells arise in distinct sectors of the telencephalon, including cortical primordium and ganglionic eminences. After the appearance of the cortical plate, further p73/Reln-IR cells originate in the medial periolfactory forebrain. In addition, p73 marks a novel cell population that appears at the choroid-cortical junction or cortical hem before the emergence of the dorsal hippocampus. A pronounced mediolateral gradient in the density of p73/Reln-IR neurons in the neocortical MZ at 8 gestational weeks suggests that a subset of CR cells migrate tangentially from cortical hem and taenia tecta into neocortical territory. This hypothesis is supported by the absence of p73-transcripts in prospective neocortex of p73-/-mice at embryonic day 12 (E12), whereas they are present in cortical hem and taenia tecta. In the p73-/- preplate, Reln is faintly expressed in a calretinin-positive cell population, not present in this form in the E12 wild-type cortex. At P2, Reln-IR CR cells are undetectable in the p73-/- cortex, whereas Reln-expression in interneurons is unchanged. Our results point to a close association between p73 and Reln in CR cells of the developing neocortex, with a partial dissociation in early preplate and basal telencephalon, and to a p73-mediated role of the cortical hem in neocortical development.

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.

The expression of estrogen receptors (ERs) in the developing and adult human brain has not been clearly established, although estrogens are crucial for neuronal differentiation, synapse formation, and cognitive functions. By using immunohistochemistry, we have studied the distribution of ER alpha and ER beta in human cerebral cortex and hippocampus from early prenatal stages to adult life. ER alpha was detected in the cortex at 9 gestational weeks (GW), with a high expression in proliferating zones and the cortical plate. The staining intensity decreased gradually during prenatal development but increased again from birth to adulthood. In contrast, ER beta was first detected at 15 GW in proliferating zones, and at 16/17 GW, numerous ER beta immunopositive cells were also observed in the cortical plate. ER beta expression persisted in the adult cortex, being widely distributed throughout cortical layers II-VI. In addition, from around 15 GW to adulthood, ER alpha and ER beta were expressed in human hippocampus mainly in pyramidal cells of Ammon's horn and in the dentate gyrus. Western blotting and immunohistochemistry in the adult cerebral cortex and hippocampus revealed lower protein expression of ER alpha compared with ER beta. Double immunostaining showed that during fetal life both ERs are expressed in neurons as well as in radial glia, although only ER alpha is expressed in the Cajal-Retzius neurons of the marginal zone. These observations demonstrate that the expression of ER alpha and ER beta displays different spatial-temporal patterns during human cortical and hippocampal development and suggest that both ERs may play distinct roles in several processes related to prenatal brain development.

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Breast cancer susceptibility gene 1 (BRCA1) is a breast and ovarian cancer tumor suppressor whose loss leads to DNA damage and defective centrosome functions. Despite its tumor suppression functions, BRCA1 is most highly expressed in the embryonic neuroepithelium when the neural progenitors are highly proliferative. To determine its functional significance, we deleted BRCA1 in the developing brain using a neural progenitor-specific driver. The phenotype is characterized by severe agenesis of multiple laminated cerebral structures affecting most notably the neocortex, hippocampus, cerebellum, and olfactory bulbs. Major phenotypes are caused by excess apoptosis, as these could be significantly suppressed by the concomitant deletion of p53. Certain phenotypes attributable to centrosomal and cell polarity functions could not be rescued by p53 deletion. A double KO with the DNA damage sensor kinase ATM was able to rescue BRCA1 loss to a greater extent than p53. Our results suggest distinct apoptotic and centrosomal functions of BRCA1 in neural progenitors, with important implications to understand the sensitivity of the embryonic brain to DNA damage, as well as the developmental regulation of brain size.

BackgroundCortical GABAergic interneurons (INs) are generated in the medial ganglionic eminence (MGE) and migrate tangentially into cortex. Because most, if not all, migrating MGE-derived INs express the neuregulin (NRG) receptor, ErbB4, we investigated influences of Nrg1 isoforms and Nrg3 on IN migration through ventral telencephalon (vTel) and within cortex.ResultsDuring IN migration, NRG expression domains and distributions of ErbB4-expressing, MGE-derived INs are complementary with minimal overlap, both in vTel and cortex. In wild-type mice, within fields of NRG expression, these INs are focused at positions of low or absent NRG expression. However, in ErbB4-/- HER4heart mutant mice in which INs lack ErbB4, these complementary patterns are degraded with considerable overlap evident between IN distribution and NRG expression domains. These findings suggest that NRGs are repellents for migrating ErbB4-expressing INs, a function supported by in vitro and in vivo experiments. First, in collagen co-cultures, MGE-derived cells preferentially migrate away from a source of secreted NRGs. Second, cells migrating from wild-type MGE explants on living forebrain slices from wild-type embryonic mice tend to avoid endogenous NRG expression domains, whereas this avoidance behavior is not exhibited by ErbB4-deficient cells migrating from MGE explants and instead they have a radial pattern with a more uniform distribution. Third, ectopic NRG expression in the IN migration pathway produced by in utero electroporation blocks IN migration and results in cortex distal to the blockade being largely devoid of INs. Finally, fewer INs reach cortex in ErbB4 mutants, indicating that NRG-ErbB4 signaling is required for directing IN migration from the MGE to cortex.ConclusionsOur results show that NRGs act as repellents for migrating ErbB4-expressing, MGE-derived GABAergic INs and that the patterned expression of NRGs funnels INs as they migrate from the MGE to their cortical destinations.

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...

In the fetal human hippocampus, Cajal-Retzius (CR) cells coexpress p73, a p53-family member involved in cell survival and apoptosis, and the glycoprotein reelin, crucial for radial migration. We distinguish two populations of putative CR cells. (1). p73/reelin expressing cells appear around 10 gestational weeks (GW) at the cortico-choroid border in the temporal horn of the lateral ventricle (the ventral cortical hem) and occupy the marginal zone (MZ) overlying the ammonic and dentate primordia. (2). Additional p73-positive cells appear from 14 GW onward in the neuroepithelium near the dentate-fimbrial boundary and spread toward the pial surface, flanking the migrating secondary dentate matrix. From 13 to 17 GW, large parts of the dentate gyrus are almost devoid of CR cells. p73/Reelin-positive CR cells appear in the MZ of the suprapyramidal blade at 16 GW and around 21 GW in the infrapyramidal blade. The p73-positive cells of the dentate-fimbrial boundary express reelin when they are close to the pial surface, suggesting that they differentiate into CR cells of the infrapyramidal blade. Reelin-positive, p73-negative interneurons are prominent in the prospective strata lacunosum-moleculare and radiatum of cornu ammonis as early as 14 GW; in the dentate molecular layer and hilus they appear around midgestation. We propose that CR cells of the human hippocampal formation belong to two distinct cell populations: an early one derived from the ventral cortical hem and mainly related to migration of the ammonic and dentate plates and a later appearing one derived from the dentate-fimbrial neuroepithelium, which may be related to the protracted neurogenesis and migration of dentate granule cells, particularly of the infrapyramidal blade.