Development, specification, and diversity of callosal projection neurons

Callosal projection neurons (CPN) are a diverse population of neocortical projection neurons that connect the two hemispheres of the cerebral cortex via the corpus callosum. They play key roles in high-level associative connectivity, and have been implicated in cognitive syndromes of high-level associative dysfunction, such as autism spectrum disorders. CPN evolved relatively recently compared to other cortical neuron populations, and have undergone disproportionately large expansion from mouse to human. While much is known about the anatomical trajectory of developing CPN axons, and progress has been made in identifying cellular and molecular controls over midline crossing, only recently have molecular-genetic controls been identified that specify CPN populations, and help define CPN subpopulations. In this review, we discuss development, diversity, and evolution of CPN.Stem Cell and Regenerative Biolog

Defining diurnal fluctuations in mouse choroid plexus and CSF at high molecular, spatial, and temporal resolution

Transmission and secretion of signals via the choroid plexus (ChP) brain barrier can modulate brain states via regulation of cerebrospinal fluid (CSF) composition. Here, we developed a platform to analyze diurnal variations in male mouse ChP and CSF. Ribosome profiling of ChP epithelial cells revealed diurnal translatome differences in metabolic machinery, secreted proteins, and barrier components. Using ChP and CSF metabolomics and blood-CSF barrier analyses, we observed diurnal changes in metabolites and cellular junctions. We then focused on transthyretin (TTR), a diurnally regulated thyroid hormone chaperone secreted by the ChP. Diurnal variation in ChP TTR depended on Bmal1 clock gene expression. We achieved real-time tracking of CSF-TTR in awake Tt

Subtype-Specific Genes that Characterize Subpopulations of Callosal Projection Neurons in Mouse Identify Molecularly Homologous Populations in Macaque Cortex

Callosal projection neurons (CPN) interconnect the neocortical hemispheres via the corpus callosum, and are implicated in associative integration of multi-modal information. CPN have undergone differential evolutionary elaboration, leading to increased diversity of cortical neurons – and more extensive and varied connections in neocortical gray and white matter – in primates compared to rodents. In mouse, distinct sets of genes are enriched in discrete subpopulations of CPN, indicating the molecular diversity of rodent CPN. Elements of rodent CPN functional and organizational diversity might thus be present in the further elaborated primate cortex. We address the hypothesis that genes controlling mouse CPN subtype diversity might reflect molecular patterns shared among mammals that arose prior to the divergence of rodents and primates. We find that, while early expression of the examined CPN-enriched genes, and post-migratory expression of these CPN-enriched genes in deep layers are highly conserved (e.g. Ptn, Nnmt, Cited2, Dkk3), by contrast, the examined genes expressed by superficial layer CPN show more variable levels of conservation (e.g. EphA3, Chn2). These results suggest that there has been evolutionarily differential retraction and elaboration of superficial layer CPN subpopulations between mouse and macaque, with independent derivation of novel populations in primates. Together, these data inform future studies regarding CPN subpopulations that are unique to primates and rodents, and indicate putative evolutionary relationships.Stem Cell and Regenerative Biolog

Directional cerebrospinal fluid movement between brain ventricles in larval zebrafish

Background Cerebrospinal fluid (CSF) contained within the brain ventricles contacts neuroepithelial progenitor cells during brain development. Dynamic properties of CSF movement may limit locally produced factors to specific regions of the developing brain. However, there is no study of in vivo CSF dynamics between ventricles in the embryonic brain. We address CSF movement using the zebrafish larva, during the major period of developmental neurogenesis. Methods CSF movement was monitored at two stages of zebrafish development: early larva [pharyngula stage; 27–30 h post-fertilization (hpf)] and late larva (hatching period; 51–54 hpf) using photoactivatable Kaede protein to calculate average maximum CSF velocity between ventricles. Potential roles for heartbeat in early CSF movement were investigated using tnnt2a mutant fish (tnnt2a [superscript −/−]) and chemical [2,3 butanedione monoxime (BDM)] treatment. Cilia motility was monitored at these stages using the Tg(βact:Arl13b–GFP) transgenic fish line. Results In wild-type early larva there is net CSF movement from the telencephalon to the combined diencephalic/mesencephalic superventricle. This movement directionality reverses at late larval stage. CSF moves directionally from diencephalic to rhombencephalic ventricles at both stages examined, with minimal movement from rhombencephalon to diencephalon. Directional movement is partially dependent on heartbeat, as indicated in assays of tnnt2a [superscript −/−] fish and after BDM treatment. Brain cilia are immotile at the early larval stage. Conclusion These data demonstrate directional movement of the embryonic CSF in the zebrafish model during the major period of developmental neurogenesis. A key conclusion is that CSF moves preferentially from the diencephalic into the rhombencephalic ventricle. In addition, the direction of CSF movement between telencephalic and diencephalic ventricles reverses between the early and late larval stages. CSF movement is partially dependent on heartbeat. At early larval stage, the absence of motile cilia indicates that cilia likely do not direct CSF movement. These data suggest that CSF components may be compartmentalized and could contribute to specialization of the early brain. In addition, CSF movement may also provide directional mechanical signaling.National Science Foundation (U.S.) (IOS-1258087)Howard Hughes Medical Institute (MIT Biology Summer internship program)Balkin-Markell-Weinberg Postdoctoral Fellowshi

Ependymal cells SCOre sweet cerebrospinal fluid.

The subcommissural organ (SCO) is a secretory tissue located on the roof of the brain's third ventricle. A new study published in PLOS Biology finds that the SCO responds to glucose by secreting signaling molecules into the cerebrospinal fluid (CSF), thereby decreasing the local ependyma-driven CSF movement

A Primer with Latest Insights

© 2020 WILEY Periodicals, Inc. The brain ventricular system is a series of connected cavities, filled with cerebrospinal fluid (CSF), that forms within the vertebrate central nervous system (CNS). The hollow neural tube is a hallmark of the chordate CNS, and a closed neural tube is essential for normal development. Development and function of the ventricular system is examined, emphasizing three interdigitating components that form a functional system: ventricle walls, CSF fluid properties, and activity of CSF constituent factors. The cellular lining of the ventricle both can produce and is responsive to CSF. Fluid properties and conserved CSF components contribute to normal CNS development. Anomalies of the CSF/ventricular system serve as diagnostics and may cause CNS disorders, further highlighting their importance. This review focuses on the evolution and development of the brain ventricular system, associated function, and connected pathologies. It is geared as an introduction for scholars with little background in the field

SOX6 controls dorsal progenitor identity and interneuron diversity during neocortical development

The neuronal diversity of the CNS emerges largely from controlled spatial and temporal segregation of cell type-specific molecular regulators. We found that the transcription factor SOX6 controls the molecular segregation of dorsal (pallial) from ventral (subpallial) telencephalic progenitors and the differentiation of cortical interneurons, regulating forebrain progenitor and interneuron heterogeneity. During corticogenesis in mice, SOX6 and SOX5 were largely mutually exclusively expressed in pallial and subpallial progenitors, respectively, and remained mutually exclusive in a reverse pattern in postmitotic neuronal progeny. Loss of SOX6 from pallial progenitors caused their inappropriate expression of normally subpallium-restricted developmental controls, conferring mixed dorsal-ventral identity. In postmitotic cortical interneurons, loss of SOX6 disrupted the differentiation and diversity of cortical interneuron subtypes, analogous to SOX5 control over cortical projection neuron development. These data indicate that SOX6 is a central regulator of both progenitor and cortical interneuron diversity during neocortical development.Stem Cell and Regenerative Biolog

Caveolin1 Identifies a Specific Subpopulation of Cerebral Cortex Callosal Projection Neurons (CPN) Including Dual Projecting Cortical Callosal/Frontal Projection Neurons (CPN/FPN)

Abstract The neocortex is composed of many distinct subtypes of neurons that must form precise subtype-specific connections to enable the cortex to perform complex functions. Callosal projection neurons (CPN) are the broad population of commissural neurons that connect the cerebral hemispheres via the corpus callosum (CC). Currently, how the remarkable diversity of CPN subtypes and connectivity is specified, and how they differentiate to form highly precise and specific circuits, are largely unknown. We identify in mouse that the lipid-bound scaffolding domain protein Caveolin 1 (CAV1) is specifically expressed by a unique subpopulation of Layer V CPN that maintain dual ipsilateral frontal projections to premotor cortex. CAV1 is expressed by over 80% of these dual projecting callosal/frontal projection neurons (CPN/FPN), with expression peaking early postnatally as axonal and dendritic targets are being reached and refined. CAV1 is localized to the soma and dendrites of CPN/FPN, a unique population of neurons that shares information both between hemispheres and with premotor cortex, suggesting function during postmitotic development and refinement of these neurons, rather than in their specification. Consistent with this, we find that Cav1 function is not necessary for the early specification of CPN/FPN, or for projecting to their dual axonal targets. CPN subtype-specific expression of Cav1 identifies and characterizes a first molecular component that distinguishes this functionally unique projection neuron population, a population that expands in primates, and is prototypical of additional dual and higher-order projection neuron subtypes