De novo monoallelic Reelin missense variants cause dominant neuronal migration disorders via a dominant-negative mechanism.

Reelin (RELN) is a secreted glycoprotein essential for cerebral cortex development. In humans, recessive RELN variants cause cortical and cerebellar malformations, while heterozygous variants were associated with epilepsy, autism, and mild cortical abnormalities. However, the functional effects of RELN variants remain unknown.

Repurposing of the multiciliation gene regulatory network in fate specification of Cajal-Retzius neurons.

Cajal-Retzius cells (CRs) are key players in cerebral cortex development, and they display a unique transcriptomic identity. Here, we use scRNA-seq to reconstruct the differentiation trajectory of mouse hem-derived CRs, and we unravel the transient expression of a complete gene module previously known to control multiciliogenesis. However, CRs do not undergo centriole amplification or multiciliation.

Diversity within olfactory sensory derivatives revealed by the contribution of Dbx1 lineages.

In vertebrates, the embryonic olfactory epithelium contains progenitors that will give rise to distinct classes of neurons, including olfactory sensory neurons (OSNs; involved in odor detection), vomeronasal sensory neurons (VSNs; responsible for pheromone sensing), and gonadotropin-releasing hormone (GnRH) neurons that control the hypothalamic-pituitary-gonadal axis. Currently, these three neuronal lineages are usually believed to emerge from uniform pools of progenitors. Here, we found that the homeodomain transcription factor Dbx1 is expressed by neurogenic progenitors in the developing and adult mouse olfactory epithelium.

Transient perinatal metabolic shifts determine neuronal survival and functional circuit formation.

Metabolic changes are essential for neurodevelopmental processes. However, little is known about how and when neuronal metabolic remodeling occurs to promote functional circuits. In this issue of Cell, Knaus et al.

Activation of the PI3K/AKT/mTOR Pathway in Cajal-Retzius Cells Leads to Their Survival and Increases Susceptibility to Kainate-Induced Seizures.

Cajal-Retzius cells (CRs) are a class of transient neurons in the mammalian cortex that play a critical role in cortical development. Neocortical CRs undergo almost complete elimination in the first two postnatal weeks in rodents and the persistence of CRs during postnatal life has been detected in pathological conditions related to epilepsy. However, it is unclear whether their persistence is a cause or consequence of these diseases.

Aberrant survival of hippocampal Cajal-Retzius cells leads to memory deficits, gamma rhythmopathies and susceptibility to seizures in adult mice.

Cajal-Retzius cells (CRs) are transient neurons, disappearing almost completely in the postnatal neocortex by programmed cell death (PCD), with a percentage surviving up to adulthood in the hippocampus. Here, we evaluate CR's role in the establishment of adult neuronal and cognitive function using a mouse model preventing Bax-dependent PCD. CRs abnormal survival resulted in impairment of hippocampus-dependent memory, associated in vivo with attenuated theta oscillations and enhanced gamma activity in the dorsal CA1.

Cajal-retzius cells: Recent advances in identity and function.

Cajal-Retzius cells (CRs) are a transient neuronal type of the developing cerebral cortex. Over the years, they have been shown or proposed to play important functions in neocortical and hippocampal morphogenesis, circuit formation, brain evolution and human pathology. Because of their short lifespan, CRs have been pictured as a purely developmental cell type, whose production and active elimination are both required for correct brain development.

Deficient adaptation to centrosome duplication defects in neural progenitors causes microcephaly and subcortical heterotopias.

Congenital microcephaly (MCPH) is a neurodevelopmental disease associated with mutations in genes encoding proteins involved in centrosomal and chromosomal dynamics during mitosis. Detailed MCPH pathogenesis at the cellular level is still elusive, given the diversity of MCPH genes and lack of comparative in vivo studies. By generating a series of CRISPR/Cas9-mediated genetic KOs, we report here that - whereas defects in spindle pole proteins (ASPM, MCPH5) result in mild MCPH during development - lack of centrosome (CDK5RAP2, MCPH3) or centriole (CEP135, MCPH8) regulators induces delayed chromosome segregation and chromosomal instability in neural progenitors (NPs).

Single-cell transcriptomics of the early developing mouse cerebral cortex disentangle the spatial and temporal components of neuronal fate acquisition.

In the developing cerebral cortex, how progenitors that seemingly display limited diversity end up producing a vast array of neurons remains a puzzling question. The prevailing model suggests that temporal maturation of progenitors is a key driver in the diversification of the neuronal output. However, temporal constraints are unlikely to account for all diversity, especially in the ventral and lateral pallium where neuronal types significantly differ from their dorsal neocortical counterparts born at the same time.

The multiple facets of Cajal-Retzius neurons.

Cajal-Retzius neurons (CRs) are among the first-born neurons in the developing cortex of reptiles, birds and mammals, including humans. The peculiarity of CRs lies in the fact they are initially embedded into the immature neuronal network before being almost completely eliminated by cell death at the end of cortical development. CRs are best known for controlling the migration of glutamatergic neurons and the formation of cortical layers through the secretion of the glycoprotein reelin.

Wiring of higher-order cortical areas: Spatiotemporal development of cortical hierarchy.

A hierarchical development of cortical areas was suggested over a century ago, but the diversity and complexity of cortical hierarchy properties have so far prevented a formal demonstration. The aim of this review is to clarify the similarities and differences in the developmental processes underlying cortical development of primary and higher-order areas. We start by recapitulating the historical and recent advances underlying the biological principle of cortical hierarchy in adults.

Specific contribution of neurons from the Dbx1 lineage to the piriform cortex.

The piriform cortex (PC) is a major cortical processing center for the sense of smell that receives direct inputs from the olfactory bulb. In mice, the PC consists of three neuronal layers, which are populated by cells with distinct developmental origins. One origin of PC neurons is the pool of Dbx1-expressing neural progenitors located in the ventral pallium at the pallial-subpallial boundary.

How Do Electric Fields Coordinate Neuronal Migration and Maturation in the Developing Cortex?

During development the vast majority of cells that will later compose the mature cerebral cortex undergo extensive migration to reach their final position. In addition to intrinsically distinct migratory behaviors, cells encounter and respond to vastly different microenvironments. These range from axonal tracts to cell-dense matrices, electrically active regions and extracellular matrix components, which may all change overtime.

Activity-dependent death of transient Cajal-Retzius neurons is required for functional cortical wiring.

Programmed cell death and early activity contribute to the emergence of functional cortical circuits. While most neuronal populations are scaled-down by death, some subpopulations are entirely eliminated, raising the question of the importance of such demise for cortical wiring. Here, we addressed this issue by focusing on Cajal-Retzius neurons (CRs), key players in cortical development that are eliminated in postnatal mice in part via Bax-dependent apoptosis.

Evolutionary Gain of Dbx1 Expression Drives Subplate Identity in the Cerebral Cortex.

Changes in transcriptional regulation through cis-regulatory elements are thought to drive brain evolution. However, how this impacts the identity of primate cortical neurons is still unresolved. Here, we show that primate-specific cis-regulatory sequences upstream of the Dbx1 gene promote human-like expression in the mouse embryonic cerebral cortex, and this imparts cell identity.

Developmental cell death regulates lineage-related interneuron-oligodendroglia functional clusters and oligodendrocyte homeostasis.

The first wave of oligodendrocyte precursor cells (firstOPCs) and most GABAergic interneurons share common embryonic origins. Cortical firstOPCs are thought to be replaced by other OPC populations shortly after birth, maintaining a consistent OPC density and making postnatal interactions between firstOPCs and ontogenetically-related interneurons unlikely. Challenging these ideas, we show that a cortical firstOPC subpopulation survives and forms functional cell clusters with lineage-related interneurons.

Extracellular Pax6 Regulates Tangential Cajal-Retzius Cell Migration in the Developing Mouse Neocortex.

The embryonic mouse cortex displays a striking low caudo-medial and high rostro-lateral graded expression of the homeoprotein transcription factor Pax6, which presents both cell autonomous and direct noncell autonomous activities. Through the genetic induction of anti-Pax6 single-chain antibody secretion, we have analyzed Pax6 noncell autonomous activity on the migration of cortical hem- and septum-derived Cajal-Retzius (CR) neurons by live imaging of flat mount developing cerebral cortices. Blocking extracellular Pax6 disrupts tangential CR cell migration patterns by decreasing the distance traveled and changing both directionality and depth at which CR cells migrate.

Kremen1-induced cell death is regulated by homo- and heterodimerization.

In multicellular organisms, cell death pathways allow the removal of abnormal or unwanted cells. Their dysregulation can lead either to excessive elimination or to inappropriate cell survival. Evolutionary constraints ensure that such pathways are strictly regulated in order to restrain their activation to the appropriate context.

Cortical developmental death: selected to survive or fated to die.

The mature cerebral cortex only contains a fraction of the cells that are generated during embryonic development. Indeed some neuronal populations are produced in excess and later subjected to partial elimination whereas others are almost completely removed during the first two postnatal weeks in mice. Although the identity of cells that disappear, the time course and mechanisms of their death are becoming reasonably well established, the meaning of producing supernumerary cells still remains elusive.

Pax3- and Pax7-mediated Dbx1 regulation orchestrates the patterning of intermediate spinal interneurons.

Transcription factors are key orchestrators of the emergence of neuronal diversity within the developing spinal cord. As such, the two paralogous proteins Pax3 and Pax7 regulate the specification of progenitor cells within the intermediate neural tube, by defining a neat segregation between those fated to form motor circuits and those involved in the integration of sensory inputs. To attain insights into the molecular means by which they control this process, we have performed detailed phenotypic analyses of the intermediate spinal interneurons (IN), namely the dI6, V0, V0 and V1 populations in compound null mutants for Pax3 and Pax7.

Targeted Inactivation of Bax Reveals a Subtype-Specific Mechanism of Cajal-Retzius Neuron Death in the Postnatal Cerebral Cortex.

Cajal-Retzius cells (CRs), the first-born neurons in the developing cerebral cortex, coordinate crucial steps in the construction of functional circuits. CRs are thought to be transient, as they disappear during early postnatal life in both mice and humans, where their abnormal persistence is associated with pathological conditions. Embryonic CRs comprise at least three molecularly and functionally distinct subtypes: septum, ventral pallium/pallial-subpallial boundary (PSB), and hem.

Reallocation of Olfactory Cajal-Retzius Cells Shapes Neocortex Architecture.

The neocortex undergoes extensive developmental growth, but how its architecture adapts to expansion remains largely unknown. Here, we investigated how early born Cajal-Retzius (CR) neurons, which regulate the assembly of cortical circuits, maintain a dense superficial distribution in the growing neocortex. We found that CR cell density is sustained by an activity-dependent importation of olfactory CR cells, which migrate into the neocortex after they have acted as axonal guidepost cells in the olfactory system.

Enhanced Abventricular Proliferation Compensates Cell Death in the Embryonic Cerebral Cortex.

Loss of neurons in the neocortex is generally thought to result in a final reduction of cerebral volume. Yet, little is known on how the developing cerebral cortex copes with death of early-born neurons. Here, we tackled this issue by taking advantage of a transgenic mouse model in which, from early embryonic stages to mid-corticogenesis, abundant apoptosis is induced in the postmitotic compartment.

Neuronal fate specification by the Dbx1 transcription factor is linked to the evolutionary acquisition of a novel functional domain.

Background: Dbx1 is a homeodomain transcription factor involved in neuronal fate specification belonging to a widely conserved family among bilaterians. In mammals, Dbx1 was proposed to act as a transcriptional repressor by interacting with the Groucho corepressors to allow the specification of neurons involved in essential biological functions such as locomotion or breathing.

Results: Sequence alignments of Dbx1 proteins from different species allowed us to identify two conserved domains related to the Groucho-dependent Engrailed repressor domain (RD), as well as a newly described domain composed of clusterized acidic residues at the C-terminus (Cter) which is present in tetrapods but also several invertebrates.