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CMFDA tracer injections into the subpallium and pallial-subpallial boundary (PSB) label cells in the pallium. (A-D) Four coronal slices from stage 15 turtle embryos were labeled from the VZ of the PSB (A), LGE (B) or MGE (C, rostral and D, caudal) with CMFDA-coated bamboo fibers (black or white stars), cultured for 5 days, fixed in PAF and immunoreacted with Darpp-32 antibodies (A,B,C,D). (A,B,C,D) Merged images (CMDFA, green; Darpp-32, red). (A) A PSB injection ventral to the DVR and dorsal to the Darpp-32-positive LGE area (A) labeled cells in the DVR and LC but not in the DC. (B) Tracer placement into the LGE labeled numerous cells oriented radially in the Darpp-32-positive area (B) and few cells in the pallium. (C,D) MGE injections ventral to the Darpp-32-positive area (C,D) labeled cells between the Darpp-32-positive LGE and DVR, in the LC and along the VZ of the DVR (C,D). A few labeled cells are present in the DC. Scale bar: 200 m. (E-H) Four coronal slices from turtle embryos at stage 17 (E-G) or 19 (H,H) were labeled with CMDFA-coated bamboo fibers (black or white stars) placed into the VZ of the PSB (E,H), LGE (F) or MGE (G) and stained for Darpp-32 (E-G) or calbindin (H) immunoreactivity after fixation. PSB placements labeled a very large number of cells in the PSB (E,H), and labeled scattered cells in the DVR and cortex (LC, DC). LGE placements at stage 17 (F) labeled numerous cells in the pallium, at the PSB and along the pallial VZ. By contrast, MGE placements (G) no longer labeled cells in the pallium, and labeled few cells along the PSB. Scale bars: 200 m in E-G; 500 m in H,H.
Source publication
Origin, timing and direction of neuronal migration during brain development determine the distinct organization of adult structures. Changes in these processes might have driven the evolution of the forebrain in vertebrates. GABAergic neurons originate from the ganglionic eminence in mammals and migrate tangentially to the cortex. We are interested...
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... contained a dense and large cluster of Darpp-32-positive cells (Fig. 2J,L). Darpp-32 is known to be expressed in embryonic rodent striatum (Guennoun and Bloch, 1992) and in the adult striatum of both turtles and mammals (Ouimet et al., 1983;Smeets et al., 2003). Therefore, Darpp-32 expression was used to localize the LGE in cultured slices (see Fig. 3). The DVR differentiates dorsal to the PSB (Fig. 2G-I, dorsal to arrows). The range in weight at each stage is given in milligrams (mg) and follows the timetable of Pieau and Dorizzi ( Pieau and Dorizzi, 1981). On average, three slice cultures were prepared from every telencephalon. The same proportion of anterior, medial and posterior ...
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... stages 15 and 16, injection of the tracker CMFDA into the same site gave a consistent pattern of labeling and so these stages were analyzed together. Subpallial CMFDA placements labeled numerous cells in the pallium, and MGE placement labeled the most numerous wave of tangentially migrating cells. Cells from the MGE (Fig. 3C,D) distributed along the ventricle in both the ventral and dorsal telencephalon, and colonized the whole lateral cortex and the lateral part of the dorsal cortex, but were not observed in the hippocampus. Surprisingly, the cell density within the mantle zone of the DVR was lower than in the neighboring cortex or in the ventricular ...
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... injections labeled numerous cells in the Darpp-32-positive sector of the striatum (Fig. 3B-B). As in stage 14 slices, CMFDA placements performed in the PSB (Fig. 3A) labeled numerous cells in the dorsal telencephalon. Again, labeled cells were less numerous within the core of the DVR than along the pia or the ventricle. Cells labeled from the PSB also distributed to the ventral embryonic ...
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... injections labeled numerous cells in the Darpp-32-positive sector of the striatum (Fig. 3B-B). As in stage 14 slices, CMFDA placements performed in the PSB (Fig. 3A) labeled numerous cells in the dorsal telencephalon. Again, labeled cells were less numerous within the core of the DVR than along the pia or the ventricle. Cells labeled from the PSB also distributed to the ventral embryonic ...
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... stage 17, the number of cells labeled from the dorsal half of the subpallium (LGE placements) increased (Fig. 3F). Cells labeled from the LGE distributed throughout the whole pallium (DVR and dorsal cortex), although their density was highest along the ventricle. At stage 17, MGE placements labeled fewer cells, mostly in the ventricular zone of the ventral and dorsal telencephalon (Fig. 3G). At later stages (18)(19), MGE tracer placements rarely ...
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... from the dorsal half of the subpallium (LGE placements) increased (Fig. 3F). Cells labeled from the LGE distributed throughout the whole pallium (DVR and dorsal cortex), although their density was highest along the ventricle. At stage 17, MGE placements labeled fewer cells, mostly in the ventricular zone of the ventral and dorsal telencephalon (Fig. 3G). At later stages (18)(19), MGE tracer placements rarely labeled cells outside the MGE, whereas LGE placements still labeled high numbers of cells in the pallium (Fig. 4). Tracing from the PSB labeled cells that were more likely to be distributed to the lateral cortex and the pial surface of the DVR (Fig. ...
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... the ventral and dorsal telencephalon (Fig. 3G). At later stages (18)(19), MGE tracer placements rarely labeled cells outside the MGE, whereas LGE placements still labeled high numbers of cells in the pallium (Fig. 4). Tracing from the PSB labeled cells that were more likely to be distributed to the lateral cortex and the pial surface of the DVR (Fig. ...
Citations
... Adult vertebrate brains reflect the differential impact of tangential migration during development (García-Moreno and Molnár 2020). In all vertebrate species that have been studied, including primates, tangentially migrating subpallial GA-BAergic neurons are present and their migration through the pallium is conserved throughout the vertebrate radiation (Cobos et al. 2001;Métin et al. 2007;Carrera et al. 2008;Moreno et al. 2008Moreno et al. , 2010García-Moreno et al. 2018). By contrast, glutamatergic intrapallial tangential migrations evolved independently (García- . ...
... Gene expression and lineage data suggests a deep conservation of the radially exclusive development of lateral ventral pallia in amniotes (Puelles et al. 2016a,b,c;Garcia-Moreno and Molnár 2020). The mammalian novelty of these early and later migratory patterns of glutamatergic neurons is in contrast with the highly conserved tangential migratorypatterns of GABAergic neuronsinsauropsids ( Fig. 4; Cobos et al. 2001;Métin et al. 2007;Carrera et al. 2008;Moreno et al. 2008;Rueda-Alaña et al. 2018;Garcia-Moreno and Molnár 2020). Molnár and Butler (2002) postulated the collopallial field hypothesis, which examined the differences in the claustro-amygdalar formation between birds, reptiles, and mammals. ...
Conscious perception in mammals depends on precise circuit connectivity between cerebral cortex and thalamus; the evolution and development of these structures are closely linked. During the wiring of reciprocal thalamus-cortex connections, thalamocortical axons (TCAs) first navigate forebrain regions that had undergone substantial evolutionary modifications. In particular, the organization of the pallial-subpallial boundary (PSPB) diverged significantly between mammals, reptiles, and birds. In mammals, transient cell populations in internal capsule and early corticofugal projections from subplate neurons closely interact with TCAs to guide pathfinding through ventral forebrain and PSPB crossing. Prior to thalamocortical axon arrival, cortical areas are initially patterned by intrinsic genetic factors. Thalamocortical axons then innervate cortex in a topographically organized manner to enable sensory input to refine cortical arealization. Here, we review the mechanisms underlying the guidance of thalamocortical axons across forebrain boundaries, the implications of PSPB evolution for thalamocortical axon pathfinding, and the reciprocal influence between thalamus and cortex during development.
... We identified 30 diverse clusters (n = 15,665 cells) of GABAergic (Gad1+/Gad2+) neuronal cells (Fig. 3, A to B) in the axolotl. In many vertebrates, GABAergic interneurons are born in the three ganglionic eminences, lateral ganglionic eminence (LGE), caudal ganglionic eminence (CGE) and medial ganglionic eminence (MGE), and migrate to the pallium during development (24,25). Comparative single cell transcriptomic analysis in mammals, lizards, turtles and songbirds have revealed that GABAergic interneurons are deeply conserved between amniote species and express shared sets of TFs (1,2). ...
... We used RNA velocity based trajectory inference (41,42) to explore the cellular and molecular dynamics of postembryonic neurogenesis. We focused our analysis on glutamatergic neurons, since these are known to be locally generated, whereas GABAergic neurons migrate across the pallium from the striatum and thus our data likely misses some corresponding progenitor populations (24,25). We focused on transitions from active ependymoglia to the most differentiated glutamatergic neurons. ...
Salamanders are important tetrapod models to study brain organization and regeneration, however the identity and evolutionary conservation of brain cell types is largely unknown. Here, we delineate cell populations in the axolotl telencephalon during homeostasis and regeneration, representing the first single-cell genomic and spatial profiling of an anamniote tetrapod brain. We identify glutamatergic neurons with similarities to amniote neurons of hippocampus, dorsal and lateral cortex, and conserved GABAergic neuron classes. We infer transcriptional dynamics and gene regulatory relationships of postembryonic, region-specific direct and indirect neurogenesis, and unravel conserved signatures. Following brain injury, ependymoglia activate an injury-specific state before reestablishing lost neuron populations and axonal connections. Together, our analyses yield key insights into the organization, evolution, and regeneration of a tetrapod nervous system.
... Lastly, the subpallium is the major supplier of cortical interneurons. In in vivo neurodevelopment, cortical interneurons migrate tangentially from the subpallium into the dorsal cortex (Guo and Anton, 2014;Marin and Rubenstein, 2001;Metin et al., 2007). ...
... During in vivo neurodevelopment, the subpallium is the major source of interneurons which follow tangential migratory routes towards the dorsal cortex (Guo and Anton, 2014;Marin and Rubenstein, 2001;Metin et al., 2007). The generation of low numbers J o u r n a l P r e -p r o o f 10 of interneurons in sliced cortical organoids suggests that these models lack a subpallium. ...
Human organoids stand at the forefront of basic and translational research, providing experimentally tractable systems to study human development and disease. These stem cell-derived, in vitro cultures can generate a multitude of tissue and organ types, including distinct brain regions and sensory systems. Neural organoid systems have provided fundamental insights into molecular mechanisms governing cell fate specification and neural circuit assembly and serve as promising tools for drug discovery and understanding disease pathogenesis. In this review, we discuss several human neural organoid systems, how they are generated, advances in 3D imaging and bioengineering, and the impact of organoid studies on our understanding of the human nervous system.
... A potential mechanism for this hypothesized cell type continuity was proposed by Chen et al. (2013), which involved tangential migration of cell types around the developing ventricle space, ultimately giving rise to the adjacent dorsal and ventral pallium populations upon occlusion. At that time, the literature had supported the presence of both radial and tangential migration of excitatory neurons in the developing avian telencephalon (Métin et al., 2007;Striedter & Keefer, 2000). However, since then the Molnar group has conducted more targeted embryonic developmental fate mapping studies to test for tangential migration and concluded that only radial migration occurs in the avian dorsal and ventral pallium domains away from the ventricle (García-Moreno et al., 2018). ...
Over the last two decades, beginning with the Avian Brain Nomenclature Forum in 2000, major revisions have been made to our understanding of the organization and nomenclature of the avian brain. However, there are still unresolved questions on avian pallial organization, particularly whether the cells above the vestigial ventricle represent distinct populations to those below it or similar populations. To test these two hypotheses, we profiled the transcriptomes of the major avian pallial subdivisions dorsal and ventral to the vestigial ventricle boundary using RNA sequencing and a new zebra finch genome assembly containing about 22,000 annotated, complete genes. We found that the transcriptomes of neural populations above and below the ventricle were remarkably similar. Each subdivision in dorsal pallium (Wulst) had a corresponding molecular counterpart in the ventral pallium (DVR). In turn, each corresponding subdivision exhibited shared gene co‐expression modules that contained gene sets enriched in functional specializations, such as anatomical structure development, synaptic transmission, signaling, and neurogenesis. These findings are more in line with the continuum hypothesis of avian brain subdivision organization above and below the vestigial ventricle space, with the pallium as a whole consisting of four major cell populations (intercalated pallium, mesopallium, hyper‐nidopallium, and arcopallium) instead of seven (hyperpallium apicale, interstitial hyperpallium apicale, intercalated hyperpallium, hyperpallium densocellare, mesopallium, nidopallium, and arcopallium). We suggest adopting a more streamlined hierarchical naming system that reflects the robust similarities in gene expression, neural connectivity motifs, and function. These findings have important implications for our understanding of overall vertebrate brain evolution.
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... The similarity of GABA-1 neurons to LGE-class neurons and their broad distribution in the songbird pallium suggest that the migration of LGE-class GABAergic neurons is more extensive in birds than in mammals (Fig. 6G). In both chickens and turtles, LGEclass neurons tangentially migrate into the DVR and dorsal pallium (82)(83)(84)(85). However, transplantation of embryonic turtle LGE into mouse embryonic slices results in the migration of GABAergic cells into the piriform cortex and amygdala but not into the neocortex (84). ...
... In both chickens and turtles, LGEclass neurons tangentially migrate into the DVR and dorsal pallium (82)(83)(84)(85). However, transplantation of embryonic turtle LGE into mouse embryonic slices results in the migration of GABAergic cells into the piriform cortex and amygdala but not into the neocortex (84). Together, these results suggest that the avian DVR and mammalian ventral pallium express signaling factors that regulate the migration and retention of LGE-class neurons. ...
The cells of songbird motor circuits
Birds have complex motor and cognitive abilities that rival or exceed the performance of many mammals, but their brains are organized in a notably different way. Parts of the bird brain have been functionally compared to the mammalian neocortex. However, it is still controversial to what extent these regions are truly homologous with the neocortex or if instead they are examples of evolutionary convergence. Colquitt et al. used single-cell sequencing to identify and characterize the major classes of neurons that comprise the song-control system in birds (see the Perspective by Tosches). They found multiple previously unknown neural classes in the bird telencephalon and shed new light on the long-standing controversy regarding the nature of homology between avian and mammalian brains.
Science , this issue p. eabd9704 ; see also p. 676
... This suggests that the emergence of these early neuronal populations in mammalian ancestors might have played a role in shaping the early development of dorsal pallium and could have triggered the evolution of the mammalian neocortex . Interestingly, inhibitory GABAergic neurons show similar tangential migratory behaviors in the reptiles and mammals (Cobos et al. 2001;Metin et al. 2007). However, excitatory pyramidal neuronal precursors of the lateral migratory stream traverse the Pax6 territory to reach lateral pallial regions in mammals but remain in situ within the DVR in sauropsids ( Figure 5.6b). ...
The cerebral cortex controls our unique higher cognitive abilities. Modifi cations to gene expression, progenitor behavior, cell lineage, and neural circuitry have accompanied evolution of the cerebral cortex. This chapter considers the progress made over the past thirty years in defi ning potential mechanisms that contribute to cortical development and evolution. It discusses the value of model systems for understanding elaboration of cortical organization in humans, with an emphasis on recent technical and conceptual advances. It then examines our current understanding of the molecular and cellular basis for cortical development and evolution; discusses how neuronal fates are specifi ed and organized in lamina, columns, and areas; and revisits the radial unit and protomap hypotheses. Finally, it considers our current understanding of the development, stability , and plasticity of cortical circuitry. Throughout, it highlights the profound impact that new technological advances have made at the molecular and cellular level, and how this has changed our understanding of cortical development and evolution. The authors conclude by identifying critical and tractable research directions to address gaps in our understanding of cortical development and evolution.
... Across several species (Lavdas et al., 1999;Metin et al., 2007;Tanaka et al., 2011;Gelman et al., 2012;Hansen et al., 2013;Ma et al., 2013;Hu et al., 2017), ganglionic eminences (GE) consisting of extensive proliferative cell masses are visible as distinct elevations adjacent to, and protruding into, lateral ventricular walls. Identification of embryonic lateral and medial GE subregions is guided by transient developmental appearance of anatomical landmarks (Brazel et al., 2003;Flames et al., 2007). ...
... Next, we performed a compartmentalized quantitative analysis of Nxk2. It is well established that MGE produces GABAergic neurons that tangentially migrate to hippocampus, cortex, striatum and thalamus (Marin and Rubenstein, 2001;Metin et al., 2007;Laclef and Metin, 2018). Next, we used down-regulation of Nkx2.1 expression in migratory cells to delineate MGE regions coupled with Lhx6 expression to track migratory cells and the transition between germinal zone and migratory routes at E35 (Fig. 4). ...
Interneurons contribute to the complexity of neural circuits and maintenance of normal brain function. Rodent interneurons originate in embryonic ganglionic eminences, but developmental origins in other species are less understood. Here, we show that transcription factor expression patterns in porcine embryonic subpallium are similar to rodents, delineating a distinct medial ganglionic eminence (MGE) progenitor domain. On the basis of Nkx2.1, Lhx6 and Dlx2 expression, in vitro differentiation into neurons expressing GABA and robust migratory capacity in explant assays, we propose that cortical and hippocampal interneurons originate from a porcine MGE region. Following xenotransplantation into adult male and female rat hippocampus, we further demonstrate that porcine MGE progenitors, like those from rodents, migrate and differentiate into morphologically distinct interneurons expressing GABA. Our findings reveal that basic rules for interneuron development are conserved across species, and that porcine embryonic MGE progenitors could serve as a valuable source for interneuron-based xenotransplantation therapies.
Significance Statement
Here we demonstrate that porcine MGE, like rodents, exhibit a distinct transcriptional and pallial interneuron-specific antibody profile, in vitro migratory capacity and are amenable to xenotransplantation. This is the first comprehensive examination of embryonic pallial interneuron origins in the pig, and because a rich neurodevelopmental literature on embryonic mouse MGE exists (with some additional characterizations in other species like monkey and human) our work allows direct neurodevelopmental comparisons with this literature.
... This is a very difficult question to answer, even after a thorough review of the bibliography, since the interspecific variations that can be found are as many as the models described. In rodents it has been reported that local inhibitory cortical interneurons represent approximately 20-30% of total neurons, and only the aspiny (or sparsely spiny) non-pyramidal cells are GABAergic neurons (Kepecs and Fishell 2014), located in all layers (Dirksen et al. 1993;Brox et al. 2003;Medina et al. 2005;Bachy and Rétaux 2006;Moreno et al. 2008a, b) and turtle (Connors and Kriegstein 1986;Blanton et al. 1987;Métin et al. 2007;Moreno et al. 2010;Tanaka and Nakajima 2012). In addition, GABAergic neurons were also observed in the pallium of other gnathostomes (Franzoni and Morino 1989;Medina et al. 1994;Veenman and Reiner 1994;Carrera et al. 2008;Mueller et al. 2008;Mueller and Guo 2009). ...
The organization of the pallial derivatives across vertebrates follows a comparable elementary arrangement, although not all of them possess a layered cortical structure as sophisticated as the cerebral cortex of mammals. However, its expansion along evolution has only been possible by the development and coevolution of the cellular networks formed by excitatory neurons and inhibitory interneurons. Thus, the comparative analysis of interneuron types in vertebrate models of key evolutionary significance will provide important information, due to the extraordinary anatomical sophistication of their interneuron systems with simpler behavioral implications. Particularly in mammals, the main consensus for classifying interneuron types is based on non-overlapping markers, which do not form a single population, but consist of several distinct classes of inhibitory cells showing co-expression of other markers. In our study, we analyzed immunohistochemically the expression of the main markers like somatostatin (SOM), parvalbumin (PV), calretinin (CR), calbindin (CB), neuropeptide Y (NPY) and/or nitric oxide synthase (NOS) at the pallial regions of three different models of Osteichthyes. First, we selected two tetrapods, one amniote from the genus Pseudemys belonging to the order Testudine, at the base of the amniote diversification and with a three-layered simple cortex, and the Anuran Xenopus laevis, an anamniote tetrapod with a non-layered evaginated pallium, and finally the order Polypteriform, a small fish group at the base of the actinopterygian diversification with an everted telencephalon. SOM was the most conserved interneuron type in terms of its distribution and co-expression with other markers such as CR, in contrast to PV, which showed a different pattern between the models analyzed. In addition, the SOM expression supports a homological relationship between the medial pallial derivatives in all the models. CR and CB expressions in the tetrapods were observed, particularly, CR expressing cells were detected in the medial and the dorsal pallial derivatives, in contrast to CB, which appeared only in discrete scattered populations. However, the pallium of Polypteriforms fishes was almost devoid of CR cells, in contrast to the important number of CB cells observed in all the pallial regions. The NPY immunoreactivity was detected in all the pallial domains of all the models, as well as cells coexpressing CR. Finally, the pallial nitrergic expression was also conserved, which allows to postulate the homological relationships between the ventropallial and the amygdaloid derivatives. In summary, even in basal pallial models the neurochemically characterized interneurons indicate that their first appearance took place before the common ancestor of amniotes. Thus, our results suggest a shared pattern of interneuron types in the pallium of all Osteichthyes.
... The postmitotic neurons that have been generated must then find their final place of destination. They obtain bipolar morphology and migrate largely orthogonal to the brain surface guided by aRGC (Métin et al., 2007). So, only after completing the last cell division and establishing their polarity, neurons begin to migrate from the VZ/SVZ. ...
Malformations of cortical development are a group of rare disorders commonly manifesting with developmental delay, cerebral palsy or seizures. The neurological outcome is extremely variable depending on the type, extent and severity of the malformation and the involved genetic pathways of brain development. Neuroimaging plays an essential role in the diagnosis of these malformations, but several issues regarding malformations of cortical development definitions and classification remain unclear. The purpose of this consensus statement is to provide standardized malformations of cortical development terminology and classification for neuroradiological pattern interpretation. A committee of international experts in paediatric neuroradiology prepared systematic literature reviews and formulated neuroimaging recommendations in collaboration with geneticists, paediatric neurologists and pathologists during consensus meetings in the context of the European Network Neuro-MIG initiative on Brain Malformations (https://www.neuro-mig.org/). Malformations of cortical development neuroimaging features and practical recommendations are provided to aid both expert and non-expert radiologists and neurologists who may encounter patients with malformations of cortical development in their practice, with the aim of improving malformations of cortical development diagnosis and imaging interpretation worldwide.
... The mammalian novelty of these early and later migratory patterns of glutamatergic neurons is in contrast with the highly conserved tangential migratory patterns of GABAergic neurons in sauropsids and all mammals from pallidum (Carrera et al., 2008;Cobos et al., 2001;Metin et al., 2007;. ...
Charles Darwin stated, “community in embryonic structure reveals community of descent”. Thus, to understand how the neocortex emerged during mammalian evolution we need to understand the evolution of the development of the pallium, the source of the neocortex. In this article, we review the variations in the development of the pallium that enabled the production of the six-layered neocortex. We propose that an accumulation of subtle modifications from very early brain development accounted for the diversification of vertebrate pallia and the origin of the neocortex. Initially, faint differences of expression of secretable morphogens promote a wide variety in the proportions and organization of sectors of the early pallium in different vertebrates. It prompted different sectors to host varied progenitors and distinct germinative zones. These cells and germinative compartments generate diverse neuronal populations that migrate and mix with each other through radial and tangential migrations in a taxon-specific fashion. Together, these early variations had a profound influence on neurogenetic gradients, lamination, positioning, and connectivity. Gene expression, hodology, and physiological properties of pallial neurons are important features to suggest homologies, but the origin of cells and their developmental trajectory are fundamental to understand evolutionary changes. Our review compares the development of the homologous pallial sectors in sauropsids and mammals, with a particular focus on cell lineage, in search of the key changes that led to the appearance of the mammalian neocortex.
