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The developing dorsomedial telencephalon includes the medial pallium, which goes on to form the hippocampus. Generating a reliable source of human hippocampal tissue is an important step for cell-based research into hippocampus-related diseases. Here we show the generation of functional hippocampal granule- and pyramidal-like neurons from self-organizing dorsomedial telencephalic tissue using human embryonic stem cells (hESCs). First, we develop a hESC culture method that utilizes bone morphogenetic protein (BMP) and Wnt signalling to induce choroid plexus, the most dorsomedial portion of the telencephalon. Then, we find that titrating BMP and Wnt exposure allowed the self-organization of medial pallium tissues. Following long-term dissociation culture, these dorsomedial telencephalic tissues give rise to Zbtb20 + /Prox1 + granule neurons and Zbtb20 + /KA1 + pyramidal neurons, both of which were electrically functional with network formation. Thus, we have developed an in vitro model that recapitulates human hippocampus development, allowing the generation of functional hippocampal granule- and pyramidal-like neurons. In vitro differentiation of human pluripotent stem cells (hPSCs) has enabled the generation of neuroectodermal tissues. Here, Sakaguchi et al. use a modified neocortical induction method to generate functional hippocampal granule and pyramidal-like neurons, as well as dorsomedial telencephalic tissues from hPSCs.

The orphan G protein-coupled receptor (GPCR) GPR124/tumor endothelial marker 5 is highly expressed in central nervous system (CNS) endothelium. Here, we show that complete null or endothelial-specific GPR124 deletion resulted in embryonic lethality from CNS-specific angiogenesis arrest in forebrain and neural tube. Conversely, GPR124 overexpression throughout all adult vascular beds produced CNS-specific hyperproliferative vascular malformations. In vivo, GPR124 functioned cell-autonomously in endothelium to regulate sprouting, migration, and developmental expression of the blood-brain barrier marker Glut1, whereas in vitro, GPR124 mediated Cdc42-dependent directional migration to forebrain-derived, vascular endothelial growth factor-independent cues. Our results demonstrate CNS-specific angiogenesis regulation by an endothelial receptor and illuminate functions of the poorly understood adhesion GPCR subfamily. Further, the functional tropism of GPR124 marks this receptor as a therapeutic target for CNS-related vascular pathologies.

Dorsoventral patterning of the telencephalon is established early in forebrain development and underlies many of the regional subdivisions that are critical to the later organization of neural circuits in the cerebral cortex and basal ganglia. Sonic hedgehog (Shh) is involved in the generation of the ventral-most telencephalic cells, but the identity of the extrinsic signal(s) that induce dorsal character in telencephalic cells is not known. Here we show in chick embryos that sequential Wnt and fibroblast growth factor (FGF) signaling specifies cells of dorsal telencephalic character.

Modeling the processes of neuronal progenitor proliferation and differentiation to produce mature cortical neuron subtypes is essential for the study of human brain development and the search for potential cell therapies. We demonstrated a novel paradigm for the generation of vascularized organoids (vOrganoids) consisting of typical human cortical cell types and a vascular structure for over 200 days as a vascularized and functional brain organoid model. The observation of spontaneous excitatory postsynaptic currents (sEPSCs), spontaneous inhibitory postsynaptic currents (sIPSCs), and bidirectional electrical transmission indicated the presence of chemical and electrical synapses in vOrganoids. More importantly, single-cell RNA-sequencing analysis illustrated that vOrganoids exhibited robust neurogenesis and that cells of vOrganoids differentially expressed genes (DEGs) related to blood vessel morphogenesis. The transplantation of vOrganoids into the mouse S1 cortex resulted in the construction of functional human-mouse blood vessels in the grafts that promoted cell survival in the grafts. This vOrganoid culture method could not only serve as a model to study human cortical development and explore brain disease pathology but also provide potential prospects for new cell therapies for nervous system disorders and injury.

Furutachi et al . identified a slowly dividing subpopulation of embryonic progenitors that later gives rise to most adult neural stem cells (NSCs) in the subependymal zone. Moreover, they found that p57 is responsible for the slow cell cycle of this embryonic population and acts causally in the emergence of adult NSCs. The mechanism by which adult neural stem cells (NSCs) are established during development is unclear. In this study, analysis of cell cycle progression by examining retention of a histone 2B (H2B)-GFP fusion protein revealed that, in a subset of mouse embryonic neural progenitor cells (NPCs), the cell cycle slows between embryonic day (E) 13.5 and E15.5 while other embryonic NPCs continue to divide rapidly. By allowing H2B-GFP expressed at E9.5 to become diluted in dividing cells until the young adult stage, we determined that a majority of NSCs in the young adult subependymal zone (SEZ) originated from these slowly dividing embryonic NPCs. The cyclin-dependent kinase inhibitor p57 is highly expressed in this embryonic subpopulation, and the deletion of p57 impairs the emergence of adult NSCs. Our results suggest that a substantial fraction of adult SEZ NSCs is derived from a slowly dividing subpopulation of embryonic NPCs and identify p57 as a key factor in generating this embryonic origin of adult SEZ NSCs.

In this study, the authors show that MGE-derived interneuron progenitors, when engrafted into the adult hippocampus, can migrate long distances and functionally integrate into the host tissue. In addition, if these cells are engrafted into the brain after the initiation of epilepsy, seizure frequency and behavioral deficits are reduced. Impaired GABA-mediated neurotransmission has been implicated in many neurologic diseases, including epilepsy, intellectual disability and psychiatric disorders. We found that inhibitory neuron transplantation into the hippocampus of adult mice with confirmed epilepsy at the time of grafting markedly reduced the occurrence of electrographic seizures and restored behavioral deficits in spatial learning, hyperactivity and the aggressive response to handling. In the recipient brain, GABA progenitors migrated up to 1,500 μm from the injection site, expressed genes and proteins characteristic for interneurons, differentiated into functional inhibitory neurons and received excitatory synaptic input. In contrast with hippocampus, cell grafts into basolateral amygdala rescued the hyperactivity deficit, but did not alter seizure activity or other abnormal behaviors. Our results highlight a critical role for interneurons in epilepsy and suggest that interneuron cell transplantation is a powerful approach to halting seizures and rescuing accompanying deficits in severely epileptic mice.

The mechanisms governing the expansion of neuron number in specific brain regions are still poorly understood. Enlarged neuron numbers in different species are often anticipated by increased numbers of progenitors dividing in the subventricular zone. Here we present live imaging analysis of radial glial cells and their progeny in the ventral telencephalon, the region with the largest subventricular zone in the murine brain during neurogenesis. We observe lineage amplification by a new type of progenitor, including bipolar radial glial cells dividing at subapical positions and generating further proliferating progeny. The frequency of this new type of progenitor is increased not only in larger clones of the mouse lateral ganglionic eminence but also in cerebral cortices of gyrated species, and upon inducing gyrification in the murine cerebral cortex. This implies key roles of this new type of radial glia in ontogeny and phylogeny. Amplification of neural progenitor cells mediates expansion of brain regions. Using imaging of progenitor cell amplification in the mouse ventral forebrain, the authors identify a new progenitor type with high frequency, which they also show to be present in expanded brain regions of other species.

This Resource chronicles dynamic gene expression patterns in the developing hypothalamus from embryonic day 10.5 through maturity. The authors find that Shh must be expressed in the hypothalamic basal plate for differentiation of the anterior and tuberal hypothalamic nuclei. The hypothalamus is a central regulator of many behaviors that are essential for survival, such as temperature regulation, food intake and circadian rhythms. However, the molecular pathways that mediate hypothalamic development are largely unknown. To identify genes expressed in developing mouse hypothalamus, we performed microarray analysis at 12 different developmental time points. We then conducted developmental in situ hybridization for 1,045 genes that were dynamically expressed over the course of hypothalamic neurogenesis. We identified markers that stably labeled each major hypothalamic nucleus over the entire course of neurogenesis and constructed a detailed molecular atlas of the developing hypothalamus. As a proof of concept of the utility of these data, we used these markers to analyze the phenotype of mice in which Sonic Hedgehog (Shh) was selectively deleted from hypothalamic neuroepithelium and found that Shh is essential for anterior hypothalamic patterning. Our results serve as a resource for functional investigations of hypothalamic development, connectivity, physiology and dysfunction.

The forebrain is the most complex region of the vertebrate central nervous system, and its developmental organisation is controversial. We fate-mapped the embryonic chick anterior neural tube and built a 4D model of brain growth. We reveal modular patterns of anisotropic growth, ascribed to progenitor regions through multiplex hybridisation chain reaction. Morphogenesis is dominated by directional growth towards the eye, more isometric expansion of the prethalamus and dorsal telencephalon, and anterior movement of ventral cells into the hypothalamus. Comparative gene expression analysis and cell mixing experiments suggest the existence of a contiguous transverse boundary region, encompassing the zona limitans intrathalamica and retromammillary hypothalamus, that divides the anterior and posterior forebrain, and becomes distorted at the base of the zona limitans intrathalamica . Fate conversion experiments indicate that the hypothalamus is topologically tripartite, lying ventral to the telencephalon, prethalamus and zona limitans intrathalamica . Our findings challenge the widely accepted prosomere model of forebrain organisation, do not support a segmented anterior forebrain, and instead suggest a ‘tripartite hypothalamus’ model. Experiments on the embryonic chick brain reveal distinct directional growth patterns and a tripartite hypothalamus, challenging the classic segmented prosomere model and offering an updated view of how the forebrain is organised.

During the second and third trimesters of human gestation, the brain undergoes rapid neurodevelopment thanks to critical processes such as neuronal migration, radial glial scaffolding, and synaptic sprouting. Unfortunately, gathering high‐quality MRI data on the healthy fetal brain is complex, making it challenging to understand this development. To address this issue, we conducted a study using motion‐corrected diffusion tensor imaging (DTI) to analyze changes in the cortical gray matter (CP) and sub‐cortical white matter (scWM) microstructure in 44 healthy fetuses between 23 and 36 weeks of gestational age. We automatically segmented these two tissues and parcellated them into eight regions based on anatomy, including the frontal, parietal, occipital, and temporal lobes, cingulate, sensory and motor cortices, and the insula. We were able to observe distinct patterns of diffusion MRI signals across these regions. Specifically, we found that in the CP, fractional anisotropy (FA) consistently decreased with age, while mean diffusivity (MD) followed a downward‐open parabolic trend. Conversely, in the scWM, FA exhibited an upward‐open parabolic trajectory, while MD followed a downward‐open parabolic trend. Our study underscores the potential for diffusion as a biomarker for normal and abnormal neurodevelopment before birth, especially since most neurodiagnostic tools are not yet available at this stage. This study utilizes advanced diffusion tensor imaging and motion correction techniques to uncover insights into the development of the fetal brain. Dynamic changes in water diffusivity and anisotropy within the fetal telencephalon offer a deeper understanding of neurodevelopmental processes. These findings underscore the regional specialization of the fetal brain.