Mammalian Telencephalon Research Articles

Spatial enhancer activation influences inhibitory neuron identity during mouse embryonic development.

The mammalian telencephalon contains distinct GABAergic projection neuron and interneuron types, originating in the germinal zone of the embryonic basal ganglia. How genetic information in the germinal zone determines cell types is unclear. Here we use a combination of in vivo CRISPR perturbation, lineage tracing and ChIP-sequencing analyses and show that the transcription factor MEIS2 favors the development of projection neurons by binding enhancer regions in projection-neuron-specific genes during mouse embryonic development. MEIS2 requires the presence of the homeodomain transcription factor DLX5 to direct its functional activity toward the appropriate binding sites. In interneuron precursors, the transcription factor LHX6 represses the MEIS2-DLX5-dependent activation of projection-neuron-specific enhancers. Mutations of Meis2 result in decreased activation of regulatory enhancers, affecting GABAergic differentiation. We propose a differential binding model where the binding of transcription factors at cis-regulatory elements determines differential gene expression programs regulating cell fate specification in the mouse ganglionic eminence.

Characterization of the Abracl-Expressing Cell Populations in the Embryonic Mammalian Telencephalon.

Abracl (ABRA C-terminal-like protein) is a small, non-typical winged-helix protein that shares similarity with the C-terminal domain of the protein ABRA (Actin-Binding Rho-Activating protein). The role of Abracl in the cell remains elusive, although in cancer cells, it has been implicated in proliferation, migration and actin dynamics. Our previous study showed that Abracl mRNA was expressed in the dividing cells of the subpallial subventricular zone (SVZ), in the developing cortical plate (CP), and in the diencephalic SVZ; however, the molecular identities of the Abracl-expressing cell populations were not defined in that work. In this study, we use double immunofluorescence to characterize the expression of Abracl on sections of embryonic murine (E11.5-E18.5) and feline (E30/31-E33/34) telencephalon; to this end, we use a battery of well-known molecular markers of cycling (Ki67, Ascl1, Dlx2) or post-mitotic (Tubb3, Gad65/67, Lhx6 and Tbr1) cells. Our experiments show that Abracl protein has, compared to the mRNA, a broader expression domain, including, apart from proliferating cells of the subpallial and diencephalic SVZ, post-mitotic cells occupying the subpallial and pallial mantle (including the CP), as well as subpallial-derived migrating interneurons. Interestingly, in late embryonic developmental stages, Abracl was also transiently detected in major telencephalic fiber tracts.

Spatiotemporal expression patterns of R-spondins and their receptors, Lgrs, in the developing mouse telencephalon

Development of the mammalian telencephalon, which is the most complex region of the central nervous system, is precisely orchestrated by many signaling molecules. Wnt signaling derived from the cortical hem, a signaling center, is crucial for telencephalic development including cortical patterning and the induction of hippocampal development. Secreted protein R-spondin (Rspo) 1–4 and their receptors, leucine-rich repeat-containing G-protein-coupled receptor (Lgr) 4–6, act as activators of Wnt signaling. Although Rspo expression in the hem during the early stages of cortical development has been reported, comparative expression analysis of Rspos and Lgr4–6 has not been performed. In this study, we examined the detailed spatiotemporal expression patterns of Rspo1–4 and Lgr4–6 in the embryonic and postnatal telencephalon to elucidate their functions. In the embryonic day (E) 10.5–14.5 telencephalon, Rspo1–3 were prominently expressed in the cortical hem. Among their receptors, Lgr4 was observed in the ventral telencephalon, and Lgr6 was highly expressed throughout the telencephalon at the same stages. This suggests that Rspo1–3 and Lgr4 initially regulate telencephalic development in restricted regions, whereas Lgr6 functions broadly. From the late embryonic stage, the expression areas of Rspo1–3 and Lgr4–6 dramatically expanded; their expression was found in the neocortex and limbic system, such as the hippocampus, amygdala, and striatum. Increased Rspo and Lgr expression from the late embryonic stages suggests broad roles of Rspo signaling in telencephalic development. Furthermore, the Lgr+ regions were located far from the Rspo+ regions, especially in the E10.5–14.5 ventral telencephalon, suggesting that Lgrs act via a Rspo-independent pathway.

Collagen XIX is required for pheromone recognition and glutamatergic synapse formation in mouse accessory olfactory bulb.

In mammals, the accessory olfactory bulb (AOB) receives input from vomeronasal sensory neurons (VSN) which detect pheromones, chemical cues released by animals to regulate the physiology or behaviors of other animals of the same species. Cytoarchitecturally, cells within the AOB are segregated into a glomerular layer (GL), mitral cell layer (MCL), and granule cell layer (GCL). While the cells and circuitry of these layers has been well studied, the molecular mechanism underlying the assembly of such circuitry in the mouse AOB remains unclear. With the goal of identifying synaptogenic mechanisms in AOB, our attention was drawn to Collagen XIX, a non-fibrillar collagen generated by neurons in the mammalian telencephalon that has previously been shown to regulate the assembly of synapses. Here, we used both a targeted mouse mutant that lacks Collagen XIX globally and a conditional allele allowing for cell-specific deletion of this collagen to test if the loss of Collagen XIX causes impaired synaptogenesis in the mouse AOB. These analyses not only revealed defects in excitatory synapse distribution in these Collagen XIX-deficient mutants, but also showed that these mutant mice exhibit altered behavioral responses to pheromones. Although this collagen has been demonstrated to play synaptogenic roles in the telencephalon, those roles are at perisomatic inhibitory synapses, results here are the first to demonstrate the function of this unconventional collagen in glutamatergic synapse formation.

Environmental Enrichment Engages Vesicular Zinc Signaling to Enhance Hippocampal Neurogenesis.

Zinc is highly concentrated in synaptic vesicles throughout the mammalian telencephalon and, in particular, the hippocampal dentate gyrus. A role for zinc in modulating synaptic plasticity has been inferred, but whether zinc has a particular role in experience-dependent plasticity has yet to be determined. The aim of the current study was to determine whether vesicular zinc is important for modulating adult hippocampal neurogenesis in an experience-dependent manner and, consequently, hippocampal-dependent behaviour. We assessed the role of vesicular zinc in modulating hippocampal neurogenesis and behaviour by comparing ZnT3 knockout (KO) mice, which lack vesicular zinc, to wild-type (WT) littermates exposed to either standard housing conditions (SH) or an enriched environment (EE). We found that vesicular zinc is necessary for a cascade of changes in hippocampal plasticity following EE, such as increases in hippocampal neurogenesis and elevations in mature brain-derived neurotrophic factor (mBDNF), but was otherwise dispensable under SH conditions. Using the Spatial Object Recognition task and the Morris Water task we show that, unlike WT mice, ZnT3 KO mice showed no improvements in spatial memory following EE. These experiments demonstrate that vesicular zinc is essential for the enhancement of adult hippocampal neurogenesis and behaviour following enrichment, supporting a role for zincergic neurons in contributing to experience-dependent plasticity in the hippocampus.

Neurogranin-like immunoreactivity in the zebrafish brain during development

Neurogranin (Nrgn) is a neural protein that is enriched in the cerebral cortex and is involved in synaptic plasticity via its interaction with calmodulin. Recently we reported its expression in the brain of the adult zebrafish (Alba-González et al. J Comp Neurol 530:1569–1587, 2022). In this study we analyze the development of Nrgn-like immunoreactivity (Nrgn-like-ir) in the brain and sensory structures of zebrafish embryos and larvae, using whole mounts and sections. First Nrgn-like positive neurons appeared by 2 day post-fertilization (dpf) in restricted areas of the brain, mostly in the pallium, epiphysis and hindbrain. Nrgn-like populations increased noticeably by 3 dpf, reaching an adult-like pattern in 6 dpf. Most Nrgn-like positive neurons were observed in the olfactory organ, retina (most ganglion cells, some amacrine and bipolar cells), pallium, lateral hypothalamus, thalamus, optic tectum, torus semicircularis, octavolateralis area, and viscerosensory column. Immunoreactivity was also observed in axonal tracts originating in Nrgn-like neuronal populations, namely, the projection of Nrgn-like immunopositive primary olfactory fibers to olfactory glomeruli, that of Nrgn-like positive pallial cells to the hypothalamus, the Nrgn-like-ir optic nerve to the pretectum and optic tectum, the Nrgn-like immunolabeled lateral hypothalamus to the contralateral region via the horizontal commissure, the octavolateralis area to the midbrain via the lateral lemniscus, and the viscerosensory column to the dorsal isthmus via the secondary gustatory tract. The late expression of Nrgn in zebrafish neurons is probably related to functional maturation of higher brain centers, as reported in the mammalian telencephalon. The analysis of Nrgn expression in the zebrafish brain suggests that it may be a useful marker for specific neuronal circuitries.

Development of the mammalian cortical hem and its derivatives: the choroid plexus, Cajal-Retzius cells and hippocampus.

The dorsal medial region of the developing mammalian telencephalon plays a central role in the patterning of the adjacent brain regions. This review describes the development of this specialized region of the vertebrate brain, called the cortical hem, and the formation of the various cells and structures it gives rise to, including the choroid plexus, Cajal-Retzius cells and the hippocampus. We highlight the ontogenic processes that create these different forebrain derivatives from their shared embryonic origin and discuss the key signalling pathways and molecules that influence the patterning of the cortical hem. These include BMP, Wnt, FGF and Shh signalling pathways acting with Homeobox factors to carve the medial telencephalon into district progenitor regions, which in turn give rise to the choroid plexus, dentate gyrus and hippocampus. We then link the formation of the lateral ventricle choroid plexus with embryonic and postnatal neurogenesis in the hippocampus.

The Polycomb group protein Ring1 regulates dorsoventral patterning of the mouse telencephalon

Dorsal-ventral patterning of the mammalian telencephalon is fundamental to the formation of distinct functional regions including the neocortex and ganglionic eminence. While Bone morphogenetic protein (BMP), Wnt, and Sonic hedgehog (Shh) signaling are known to determine regional identity along the dorsoventral axis, how the region-specific expression of these morphogens is established remains unclear. Here we show that the Polycomb group (PcG) protein Ring1 contributes to the ventralization of the mouse telencephalon. Deletion of Ring1b or both Ring1a and Ring1b in neuroepithelial cells induces ectopic expression of dorsal genes, including those for BMP and Wnt ligands, as well as attenuated expression of the gene for Shh, a key morphogen for ventralization, in the ventral telencephalon. We observe PcG protein–mediated trimethylation of histone 3 at lysine-27 and binding of Ring1B at BMP and Wnt ligand genes specifically in the ventral region. Furthermore, forced activation of BMP or Wnt signaling represses Shh expression. Our results thus indicate that PcG proteins suppress BMP and Wnt signaling in a region-specific manner and thereby allow proper Shh expression and development of the ventral telencephalon.

Common and Distinct Features of Adult Neurogenesis and Regeneration in the Telencephalon of Zebrafish and Mammals.

In contrast to mammals, the adult zebrafish brain shows neurogenic activity in a multitude of niches present in almost all brain subdivisions. Irrespectively, constitutive neurogenesis in the adult zebrafish and mouse telencephalon share many similarities at the cellular and molecular level. However, upon injury during tissue repair, the situation is entirely different. In zebrafish, inflammation caused by traumatic brain injury or by induced neurodegeneration initiates specific and distinct neurogenic programs that, in combination with signaling pathways implicated in constitutive neurogenesis, quickly, and efficiently overcome the loss of neurons. In the mouse brain, injury-induced inflammation promotes gliosis leading to glial scar formation and inhibition of regeneration. A better understanding of the regenerative mechanisms occurring in the zebrafish brain could help to develop new therapies to combat the debilitating consequences of brain injury, stroke, and neurodegeneration. The aim of this review is to compare the properties of neural progenitors and the signaling pathways, which control adult neurogenesis and regeneration in the zebrafish and mammalian telencephalon.

Distribution, number, and certain neurochemical identities of infracortical white matter neurons in the brains of three megachiropteran bat species.

A large population of infracortical white matter neurons, or white matter interstitial cells (WMICs), are found within the subcortical white matter of the mammalian telencephalon. We examined WMICs in three species of megachiropterans, Megaloglossus woermanni, Casinycteris argynnis, and Rousettus aegyptiacus, using immunohistochemical and stereological techniques. Immunostaining for neuronal nuclear marker (NeuN) revealed substantial numbers of WMICs in each species-M. woermanni 124,496 WMICs, C. argynnis 138,458 WMICs, and the larger brained R. aegyptiacus having an estimated WMIC population of 360,503. To examine the range of inhibitory neurochemical types we used antibodies against parvalbumin, calbindin, calretinin, and neural nitric oxide synthase (nNOS). The calbindin and nNOS immunostained neurons were the most commonly observed, while those immunoreactive for calretinin and parvalbumin were sparse. The proportion of WMICs exhibiting inhibitory neurochemical profiles was ~26%, similar to that observed in previously studied primates. While for the most part the WMIC population in the megachiropterans studied was similar to that observed in other mammals, the one feature that differed was the high proportion of WMICs immunoreactive to calbindin, whereas in primates (macaque monkey, lar gibbon and human) the highest proportion of inhibitory WMICs contain calretinin. Interestingly, there appears to be an allometric scaling of WMIC numbers with brain mass. Further quantitative comparative work across more mammalian species will reveal the developmental and evolutionary trends associated with this infrequently studied neuronal population.

Baicalin exerts antidepressant effects through Akt/FOXG1 pathway promoting neuronal differentiation and survival

Background and aimsImpaired neurogenesis in hippocampus may contribute to a variety of neurological diseases, such as Alzheimer's disease and depression. Baicalin (BA), which is mainly isolated from the root Scutellaria baicalensis Georgi (traditional Chinese herb), which was reported to facilitate neurogenesis, but how to play the role and the underlying molecular mechanisms are still unknown. Main methodsIn this study, we adopted the chronic unpredictable mild stress (CUMS)-induced mouse model of depression, and then explore antidepressant-like effects and possible molecular mechanisms. Key findingsWe found that BA significantly increased sucrose consumption in sucrose preference test, the number of crossing in open filed test and attenuated immobility time in tail suspension test. Additionally, BA administration notably promoted neuronal differentiation and the number of DCX+ cells. Moreover, BA facilitated immature neurons develop into mature neurons and their survival. FOXG1, a transcription factor gene, which is crucial for mammalian telencephalon development, specifically stimulates dendrite elongation. BA could reverse the decrease of p-Akt, FOXG1 and FGF2 caused by CUMS-induced. Additionally, the expression of FOXG1 and FGF2 significantly decreased when the Akt pathway were inhibited by LY294002 in SH-SY5Y cells. Interestingly, BA failed to counteract the decline. SignificanceThese results suggest that BA could promote the differentiation of neurons, which transformation into mature neurons and their survival via the Akt/FOXG1 pathway to exert antidepressant effects.

A triheptanoin-supplemented diet rescues hippocampal hyperexcitability and seizure susceptibility in FoxG1+/− mice

The Forkhead Box G1 (FOXG1) gene encodes a transcription factor with an essential role in mammalian telencephalon development. FOXG1-related disorders, caused by deletions, intragenic mutations or duplications, are usually associated with severe intellectual disability, autistic features, and, in 87% of subjects, epileptiform manifestations. In a subset of patients with FoxG1 mutations, seizures remain intractable, prompting the need for novel therapeutic options. To address this issue, we took advantage of a haploinsufficient animal model, the FoxG1+/− mouse. In vivo electrophysiological analyses of FoxG1+/− mice detected hippocampal hyperexcitability, which turned into overt seizures upon delivery of the proconvulsant kainic acid, as confirmed by behavioral observations. These alterations were associated with decreased expression of the chloride transporter KCC2.Next, we tested whether a triheptanoin-based anaplerotic diet could have an impact on the pathological phenotype of FoxG1+/− mice. This manipulation abated altered neural activity and normalized enhanced susceptibility to proconvulsant-induced seizures, in addition to rescuing altered expression of KCC2 and increasing the levels of the GABA transporter vGAT. In conclusion, our data show that FoxG1 haploinsufficiency causes dysfunction of hippocampal circuits and increases the susceptibility to a proconvulsant insult, and that these alterations are rescued by triheptanoin dietary treatment.

Alterations in the Neurobehavioral Phenotype and ZnT3/CB-D28k Expression in the Cerebral Cortex Following Lithium-Pilocarpine-Induced Status Epilepticus: the Ameliorative Effect of Leptin.

Zinc transporter 3 (ZnT3)-dependent "zincergic" vesicular zinc accounts for approximately 20% of the total zinc content of the mammalian telencephalon. Elevated hippocampal ZnT3 expression is acknowledged to be associated with mossy fiber sprouting and cognitive deficits. However, no studies have compared the long-term neurobehavioral phenotype with the expression of ZnT3 in the cerebral cortex following status epilepticus (SE). The aim of this study was to investigate changes in the long-term neurobehavioral phenotype as well as the expression of ZnT3 and calcium homeostasis-related CB-D28k in the cerebral cortex of rats subjected to neonatal SE and to determine the effects of leptin treatment immediately after neonatal SE. Fifty Sprague-Dawley rats (postnatal day 6, P6) were randomly assigned to two groups: the pilocarpine hydrochloride-induced status epilepticus group (RS, n = 30) and control group (n = 20). Rats were further divided into the control group without leptin (Control), control-plus-leptin treatment group (Leptin), RS group without leptin treatment (RS), and RS-plus-leptin treatment group (RS + Leptin). On P6, all rats in the RS group and RS + Leptin group were injected intraperitoneally (i.p.) with lithium chloride (5mEq/kg). Pilocarpine (320mg/kg, i.p.) was administered 30min after the scopolamine methyl chloride (1mg/kg) injection on P7. From P8 to P14, animals of the Leptin group and RS + Leptin group were given leptin (4mg/kg/day, i.p.). The neurological behavioral parameters (negative geotaxis reaction reflex, righting reflex, cliff avoidance reflex, forelimb suspension reflex, and open field test) were observed from P23 to P30. The protein levels of ZnT3 and CB-D28k in the cerebral cortex were detected subsequently by the western blot method. Pilocarpine-treated neonatal rats showed long-term abnormal neurobehavioral parameters. In parallel, there was a significantly downregulated protein level of CB-D28k and upregulated protein level of ZnT3 in the cerebral cortex of the RS group. Leptin treatment soon after epilepticus for 7 consecutive days counteracted these abnormal changes. Taken together with the results from our previous reports on another neonatal seizure model, which showed a significant positive inter-relationship between ZnT3 and calcium/calmodulin-dependent protein kinase IIα (CaMKIIα), the data here suggest that ZnT3/CB-D28k-associated Zn (2+)/Ca(2+) signaling might be involved in neonatal SE-induced long-term brain damage in the aspects of neurobehavioral impairment. Moreover, consecutive leptin treatment is effect at counteracting these hyperexcitability-related changes, suggesting a potential clinical significance.

Brain Evolution: Intelligence without a Cortex

Birds are capable of high level cognition even though their telencephalon is organized into nuclear groups rather than a six-layered cortex as in the mammalian brain. New data show that, despite their different macroscale organization, the circuitries of avian and mammalian telencephalon are fundamentally similar and may therefore carry out equivalent computations.

Maintenance of Positional Identity of Neural Progenitors in the Embryonic and Postnatal Telencephalon.

Throughout embryonic development and into postnatal life, regionally distinct populations of neural progenitor cells (NPCs) collectively generate the many different types of neurons that underlie the complex structure and function of the adult mammalian brain. At very early stages of telencephalic development, NPCs become organized into regional domains that each produce different subsets of neurons. This positional identity of NPCs relates to the regional expression of specific, fate-determining homeodomain transcription factors. As development progresses, the brain undergoes vast changes in both size and shape, yet important aspects of NPC positional identity persist even into the postnatal brain. How can NPC positional identity, which is established so early in brain development, endure the many dynamic, large-scale and complex changes that occur over a relatively long period of time? In this Perspective article, we review data and concepts derived from studies in Drosophila regarding the function of homeobox (Hox) genes, Polycomb group (PcG) and trithorax group (trxG) chromatin regulators. We then discuss how this knowledge may contribute to our understanding of the maintenance of positional identity of NPCs in the mammalian telencephalon. Similar to the axial body plan of Drosophila larvae, there is a segmental nature to NPC positional identity, with loss of specific homeodomain transcription factors causing homeotic-like shifts in brain development. Finally, we speculate about the role of mammalian PcG and trxG factors in the long-term maintenance of NPC positional identity and certain neurodevelopmental disorders.

Murine pluripotent stem cells with a homozygous knockout of Foxg1 show reduced differentiation towards cortical progenitors in vitro

Foxg1 is a transcription factor critical for the development of the mammalian telencephalon. Foxg1 controls the proliferation of dorsal telencephalon progenitors and the specification of the ventral telencephalon. Homozygous knockout of Foxg1 in mice leads to severe microcephaly, attributed to premature differentiation of telencephalic progenitors, mainly of cortical progenitors.Here, we analyzed the influence of a Foxg1 knockout on differentiation of murine pluripotent stem cells (mPSCs) in an in vitro model of neuronal development. Murine PSCs were prone to neuronal differentiation in embryoid body like culture with minimal medium conditions, based on the intrinsic default of PSCs to develop into cortical progenitors. Differences between Foxg1 wildtype (Foxg1WT) and knockout (Foxg1KO) mPSCs were analyzed.Several mPSC lines with homozygous mutations in Foxg1 were produced using the CRISPR/Cas9 system leading to loss of functional domains. Analysis of mRNA expression using quantitative Real-Time (q) PCR revealed that Foxg1KO mPSCs expressed significantly less mRNA of Foxg1, Emx1, and VGlut1 compared to Foxg1WT controls, indicating reduced differentiation towards dorsal telencephalic progenitors. However, the size of the derived EB-like structures did not differ between Foxg1WT and Foxg1KO mPSCs.These results show that loss of dorsal telencephalic progenitors can be detected using a simple and rapid differentiation protocol. This study is a first hint that this differentiation method can be used to analyze even extreme phenotypes that are lethal in vivo.

Loss of Interneuron-Derived Collagen XIX Leads to a Reduction in Perineuronal Nets in the Mammalian Telencephalon.

Perineuronal nets (PNNs) are lattice-like supramolecular assemblies of extracellular glycoproteins that surround subsets of neuronal cell bodies in the mammalian telencephalon. PNNs emerge at the end of the critical period of brain development, limit neuronal plasticity in the adult brain, and are lost in a variety of complex brain disorders diseases, including schizophrenia. The link between PNNs and schizophrenia led us to question whether neuronally expressed extracellular matrix (ECM) molecules associated with schizophrenia contribute to the assembly of these specialized supramolecular ECM assemblies. We focused on collagen XIX—a minor, nonfibrillar collagen expressed by subsets of telencephalic interneurons. Genetic alterations in the region encoding collagen XIX have been associated with familial schizophrenia, and loss of this collagen in mice results in altered inhibitory synapses, seizures, and the acquisition of schizophrenia-related behaviors. Here, we demonstrate that loss of collagen XIX also results in a reduction of telencephalic PNNs. Loss of PNNs was accompanied with reduced levels of aggrecan (Acan), a major component of PNNs. Despite reduced levels of PNN constituents in collagen XIX-deficient mice (col19a1−/−), we failed to detect reduced expression of genes encoding these ECM molecules. Instead, we discovered a widespread upregulation of extracellular proteases capable of cleaving Acan and other PNN constituents in col19a1−/− brains. Taken together, these results suggest a mechanism by which the loss of collagen XIX speeds PNN degradation and they identify a novel mechanism by which the loss of collagen XIX may contribute to complex brain disorders.

Apical versus Basal Neurogenesis Directs Cortical Interneuron Subclass Fate.

Fate determination in the mammalian telencephalon, with its diversity of neuronal subtypes and relevance to neuropsychiatric disease, remains a critical area of study in neuroscience. Most studies investigating this topic focus on the diversity of neural progenitors within spatial and temporal domains along the lateral ventricles. Often overlooked is whether the location of neurogenesis within a fate-restricted domain is associated with, or instructive for, distinct neuronal fates. Here, we use in vivo fate mapping and the manipulation of neurogenic location to demonstrate that apical versus basal neurogenesis influences the fate determination of major subgroups of cortical interneurons derived from the subcortical telencephalon. Somatostatin-expressing interneurons arise mainly from apical divisions along the ventricular surface, whereas parvalbumin-expressing interneurons originate predominantly from basal divisions in the subventricular zone. As manipulations that shift neurogenic location alter interneuron subclass fate, these results add an additional dimension to the spatial-temporal determinants of neuronal fate determination.

FoxP2 protein levels regulate cell morphology changes and migration patterns in the vertebrate developing telencephalon.

In the mammalian telencephalon, part of the progenitor cells transition from multipolar to bipolar morphology as they invade the mantle zone. This associates with changing patterns of radial migration. However, the molecules implicated in these morphology transitions are not well known. In the present work, we analyzed the function of FoxP2 protein in this process during telencephalic development in vertebrates. We analyzed the expression of FoxP2 protein and its relation with cell morphology and migratory patterns in mouse and chicken developing striatum. We observed FoxP2 protein expressed in a gradient from the subventricular zone to the mantle layer in mice embryos. In the FoxP2 low domain cells showed multipolar migration. In the striatal mantle layer where FoxP2 protein expression is higher, cells showed locomoting migration and bipolar morphology. In contrast, FoxP2 showed a high and homogenous expression pattern in chicken striatum, thus bipolar morphology predominated. Elevation of FoxP2 in the striatal subventricular zone by in utero electroporation promoted bipolar morphology and impaired multipolar radial migration. In mouse cerebral cortex we obtained similar results. FoxP2 promotes transition from multipolar to bipolar morphology by means of gradiental expression in mouse striatum and cortex. Together these results indicate a role of FoxP2 differential expression in cell morphology control of the vertebrate telencephalon.

Telocytes, exosomes, gap junctions and the cytoskeleton: the makings of a primitive nervous system?

THE FACTS Telocytes (TCs) form a remarkable new cell species found in many types of tissue. They were discovered by Professor Laurentiu-Mircea Popescu of Roumania in 2005 (Popescu et al., 2005), and are characterized by having very small cell bodies (consisting of a nucleus and a small amount of cytoplasm) and “extremely long and thin” tubular processes called telopodes (up to 100 micrometers long, yet only 20–200 nanometers wide). Telopodes consist of long thin tubes (called podomers) interspersed with short dilations (called podoms) that have the appearance of axonal boutons en passage. Podoms contain abundant mitochondria, calveoli and endoplasmic reticulum (Cretoiu et al., 2012a, 2013). TCs form a dense convoluted network linking TCs with each other, and with many other cell types including secretory acini and exocrine epithelial ducts, nerve fibers, macrophages, and blood vessels (Nicolescu et al., 2012; Popescu et al., 2012; Bosco et al., 2013). Gherghiceanu and Popescu (2012) report that TCs make contact with virtually all types of cells in the human heart including Schwann cells, endothelial cells, pericytes, macrophages, mast cells, fibroblasts, stem cells/progenitors, and working cardiomyocytes. In the urinary system they establish numerous contacts inter alia with macrophages in the sub-capsular space of the kidney, or with smooth muscle cells, nerve endings as well as blood capillaries in the ureter and urinary bladder (Zheng et al., 2012). In the esophagus the cells that they make contact with include macrophages and lymphocytes (Chen et al., 2013). In the small intestine TCs encircle muscle bundles, nerve structures, blood vessels, fundi of gastric glands and intestinal crypts Vannucchi et al. (2013). These networks contain embedded stem cells (Luesma et al., 2013). Connections by TCs with all of the aforementioned entities are made both by electron-dense nanocontacts involving junctions, and via exosomes (Nicolescu et al., 2012; Popescu et al., 2012; Luesma et al., 2013). Exosome release occurs along the telopodes (Cretoiu et al., 2012b). In the eye this gap-junction-linked network is prominent in the uvea and sclera. Moreover, exosomes (with a diameter up to 100 nm) are delivered by TCs to a wide variety of cells including cells of the iris stroma (Luesma et al., 2013), leading these authors to suggest that TCs may be involved in integrating neural, vascular and endocrine processes. Several authors have suggested that TCs are involved in tissue protection, remodeling and regeneration (Xiao et al., 2013; Zhao et al., 2013; Zheng et al., 2013) as well as mechanical support, spatial relationships with different cell types, intercellular signaling and modulation of intestinal motility (Cretoiu et al., 2013; Milia et al., 2013). Their presence in the meninges and in the choroid plexus/subventricular zone within the proximity of neural stem cells led Popescu et al. (2012) to suggest that TCs may be involved in modulating neural stem cell fate. Ongoing investigations are revealing increasingly important roles for TCs in the stabilization of healthy tissue function, so as to minimize inflammatory tissue damage and possibly oxidative damage to particular organs (Haines et al., 2013). For example, Zhao et al. reported an inverse correlation between the magnitude of infracted zones of rat myocardium and cardiac TC density (Zhao et al., 2013). TCs, therefore, function in tandem with stem cells in anatomical locations designated “stem-cell niches” resulting in an enhancement of their engraftment capability (Polykandriotis et al., 2010). Ceafalan et al. (2012) have suggested that TCs are involved in skin homeostasis, remodeling, regeneration and repair. It is of interest to note that, on a micro scale, a TC shares some of the properties of the claustrum (a nucleus in the mammalian telencephalon), namely, keeping its fingers in many pies, therein elevating the role and prospective benefits of gap junctions and a thin topology (Smythies et al., 2012, 2014). Both structures seem to be closely involved in integrating the function of multiple other structures.