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1.
Cell ; 186(9): 1819-1821, 2023 04 27.
Article in English | MEDLINE | ID: mdl-37116467

ABSTRACT

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. demonstrate that a temporary perinatal shift in metabolites and lipids is crucial for cortical neurons' survival and wiring.


Subject(s)
Neurons , Cell Survival , Neuronal Plasticity/physiology , Neurons/physiology
2.
Development ; 148(11)2021 06 01.
Article in English | MEDLINE | ID: mdl-34047341

ABSTRACT

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. However, they have been shown to play numerous additional key roles at many steps of cortical development, spanning from patterning and sizing functional areas to synaptogenesis. The use of genetic lineage tracing has allowed the discovery of their multiple ontogenetic origins, migratory routes, expression of molecular markers and death dynamics. Nowadays, single-cell technologies enable us to appreciate the molecular heterogeneity of CRs with an unprecedented resolution. In this Review, we discuss the morphological, electrophysiological, molecular and genetic criteria allowing the identification of CRs. We further expose the various sources, migration trajectories, developmental functions and death dynamics of CRs. Finally, we demonstrate how the analysis of public transcriptomic datasets allows extraction of the molecular signature of CRs throughout their transient life and consider their heterogeneity within and across species.


Subject(s)
Nerve Tissue Proteins/metabolism , Neurons/metabolism , Animals , Cell Adhesion Molecules, Neuronal , Cell Death , Cerebral Cortex/growth & development , Extracellular Matrix Proteins , Hippocampus/growth & development , Humans , Nerve Tissue Proteins/genetics , Neurogenesis/physiology , Neurons/cytology , Reelin Protein , Serine Endopeptidases , Transcriptome
3.
Development ; 148(14)2021 07 15.
Article in English | MEDLINE | ID: mdl-34170322

ABSTRACT

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. In this study, we implemented single-cell RNAseq to sample the diversity of progenitors and neurons along the dorso-ventral axis of the early developing pallium. We first identified neuronal types, mapped them on the tissue and determined their origin through genetic tracing. We characterised progenitor diversity and disentangled the gene modules underlying temporal versus spatial regulations of neuronal specification. Finally, we reconstructed the developmental trajectories followed by ventral and dorsal pallial neurons to identify lineage-specific gene waves. Our data suggest a model by which discrete neuronal fate acquisition from a continuous gradient of progenitors results from the superimposition of spatial information and temporal maturation.


Subject(s)
Cerebral Cortex/metabolism , Neurons/metabolism , Transcriptome , Animals , Cell Differentiation/physiology , Cerebral Cortex/pathology , Embryo, Mammalian , Female , Forkhead Transcription Factors , Gene Expression Regulation, Developmental , Homeodomain Proteins/metabolism , Mice , Mice, Inbred C57BL , Nerve Tissue Proteins , Neurogenesis/physiology , Proto-Oncogene Proteins/metabolism
4.
Semin Cell Dev Biol ; 118: 35-49, 2021 10.
Article in English | MEDLINE | ID: mdl-34034988

ABSTRACT

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. We then revisit the arguments for a hierarchical maturation of cortical areas, and further integrate the principles of cortical areas specification during embryonic and postnatal development. We highlight how the dramatic expansion in cortical size might have contributed to the increased number of association areas sustaining cognitive complexification in evolution. Finally, we summarize the recent observations of an alteration of cortical hierarchy in neuropsychiatric disorders and discuss their potential developmental origins.


Subject(s)
Cerebral Cortex/growth & development , Animals , Humans , Spatio-Temporal Analysis
5.
Int J Mol Sci ; 24(6)2023 Mar 11.
Article in English | MEDLINE | ID: mdl-36982451

ABSTRACT

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. To decipher the molecular mechanisms involved in CR death, we investigated the contribution of the PI3K/AKT/mTOR pathway as it plays a critical role in cell survival. We first showed that this pathway is less active in CRs after birth before massive cell death. We also explored the spatio-temporal activation of both AKT and mTOR pathways and reveal area-specific differences along both the rostro-caudal and medio-lateral axes. Next, using genetic approaches to maintain an active pathway in CRs, we found that the removal of either PTEN or TSC1, two negative regulators of the pathway, lead to differential CR survivals, with a stronger effect in the Pten model. Persistent cells in this latter mutant are still active. They express more Reelin and their persistence is associated with an increase in the duration of kainate-induced seizures in females. Altogether, we show that the decrease in PI3K/AKT/mTOR activity in CRs primes these cells to death by possibly repressing a survival pathway, with the mTORC1 branch contributing less to the phenotype.


Subject(s)
Kainic Acid , Proto-Oncogene Proteins c-akt , Animals , Female , Kainic Acid/toxicity , Proto-Oncogene Proteins c-akt/metabolism , Phosphatidylinositol 3-Kinases/metabolism , TOR Serine-Threonine Kinases/metabolism , Seizures/chemically induced , Mammals/metabolism
6.
Nature ; 500(7460): 85-8, 2013 Aug 01.
Article in English | MEDLINE | ID: mdl-23812590

ABSTRACT

All forms of locomotion are repetitive motor activities that require coordinated bilateral activation of muscles. The executive elements of locomotor control are networks of spinal neurons that determine gait pattern through the sequential activation of motor-neuron pools on either side of the body axis. However, little is known about the constraints that link left-right coordination to locomotor speed. Recent advances have indicated that both excitatory and inhibitory commissural neurons may be involved in left-right coordination. But the neural underpinnings of this, and a possible causal link between these different groups of commissural neurons and left-right alternation, are lacking. Here we show, using intersectional mouse genetics, that ablation of a group of transcriptionally defined commissural neurons--the V0 population--leads to a quadrupedal hopping at all frequencies of locomotion. The selective ablation of inhibitory V0 neurons leads to a lack of left-right pattern at low frequencies, mixed coordination at medium frequencies, and alternation at high locomotor frequencies. When ablation is targeted to excitatory V0 neurons, left-right alternation is present at low frequencies, and hopping is restricted to medium and high locomotor frequencies. Therefore, the intrinsic logic of the central control of locomotion incorporates a modular organization, with two subgroups of V0 neurons required for the existence of left-right alternating modes at different speeds of locomotion. The two molecularly distinct sets of commissural neurons may constrain species-related naturally occurring frequency-dependent coordination and be involved in the evolution of different gaits.


Subject(s)
Extremities/physiology , Functional Laterality/physiology , Locomotion/physiology , Nerve Net/physiology , Neurons/physiology , Animals , Functional Laterality/genetics , Gait/genetics , Gait/physiology , Homeodomain Proteins/genetics , Homeodomain Proteins/metabolism , Locomotion/genetics , Mice , Neural Inhibition , Spinal Nerves/cytology , Spinal Nerves/physiology
7.
Dev Biol ; 432(1): 24-33, 2017 12 01.
Article in English | MEDLINE | ID: mdl-28625870

ABSTRACT

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, V0D, V0VCG and V1 populations in compound null mutants for Pax3 and Pax7. This has revealed that the levels of Pax3/7 proteins determine both the dorso-ventral extent and the number of cells produced in each subpopulation; with increasing levels leading to the dorsalisation of their fate. Furthermore, thanks to the examination of mutants in which Pax3 transcriptional activity is skewed either towards repression or activation, we demonstrate that this cell diversification process is mainly dictated by Pax3/7 ability to repress gene expression. Consistently, we show that Pax3 and Pax7 inhibit the expression of Dbx1 and of its repressor Prdm12, fate determinants of the V0 and V1 interneurons, respectively. Notably, we provide evidence for the activity of several cis-regulatory modules of Dbx1 to be sensitive to Pax3 and Pax7 transcriptional activity levels. Altogether, our study provides insights into how the redundancy within a TF family, together with discrete dynamics of expression profiles of each member, are exploited to generate cellular diversity. Furthermore, our data supports the model whereby cell fate choices in the neural tube do not rely on binary decisions but rather on inhibition of multiple alternative fates.


Subject(s)
Homeodomain Proteins/physiology , Interneurons/physiology , Nerve Tissue Proteins/physiology , PAX3 Transcription Factor/physiology , PAX7 Transcription Factor/physiology , Spinal Cord/cytology , Animals , Cell Differentiation/physiology , Chick Embryo , Gene Expression Regulation, Developmental , Interneurons/cytology , Mice , Neural Tube/physiology , Spinal Cord/embryology , Stem Cells/cytology , Stem Cells/physiology
8.
Development ; 142(19): 3416-28, 2015 Oct 01.
Article in English | MEDLINE | ID: mdl-26443638

ABSTRACT

V1 interneurons are inhibitory neurons that play an essential role in vertebrate locomotion. The molecular mechanisms underlying their genesis remain, however, largely undefined. Here, we show that the transcription factor Prdm12 is selectively expressed in p1 progenitors of the hindbrain and spinal cord in the frog embryo, and that a similar restricted expression profile is observed in the nerve cord of other vertebrates as well as of the cephalochordate amphioxus. Using frog, chick and mice, we analyzed the regulation of Prdm12 and found that its expression in the caudal neural tube is dependent on retinoic acid and Pax6, and that it is restricted to p1 progenitors, due to the repressive action of Dbx1 and Nkx6-1/2 expressed in the adjacent p0 and p2 domains. Functional studies in the frog, including genome-wide identification of its targets by RNA-seq and ChIP-Seq, reveal that vertebrate Prdm12 proteins act as a general determinant of V1 cell fate, at least in part, by directly repressing Dbx1 and Nkx6 genes. This probably occurs by recruiting the methyltransferase G9a, an activity that is not displayed by the amphioxus Prdm12 protein. Together, these findings indicate that Prdm12 promotes V1 interneurons through cross-repressive interactions with Dbx1 and Nkx6 genes, and suggest that this function might have only been acquired after the split of the vertebrate and cephalochordate lineages.


Subject(s)
Carrier Proteins/metabolism , Gene Expression Regulation, Developmental/physiology , Morphogenesis/physiology , Nerve Tissue Proteins/metabolism , Renshaw Cells/physiology , Xenopus/embryology , Animals , Base Sequence , Chick Embryo , Chromatin Immunoprecipitation , Computational Biology , DNA Primers/genetics , DNA, Complementary/genetics , Gene Expression Regulation, Developmental/genetics , Homeodomain Proteins/metabolism , Immunohistochemistry , In Situ Hybridization , Mice , Molecular Sequence Data , Rhombencephalon/metabolism , Sequence Analysis, RNA , Species Specificity , Spinal Cord/metabolism
9.
Cereb Cortex ; 27(10): 4701-4718, 2017 10 01.
Article in English | MEDLINE | ID: mdl-27620979

ABSTRACT

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. Unexpectedly, the thickness of the mutant cortical plate at E18.5 was normal, due to an overproduction of upper layer neurons at E14.5. We developed and simulated a mathematical model to investigate theoretically the recovering capacity of the system and found that a minor increase in the probability of proliferative divisions of intermediate progenitors (IPs) is a powerful compensation lever. We confirmed experimentally that mutant mice showed an enhanced number of abventricular progenitors including basal radial glia-like cells and IPs. The latter displayed increased proliferation rate, sustained Pax6 expression and shorter cell cycle duration. Altogether, these results demonstrate the remarkable plasticity of neocortical progenitors to adapt to major embryonic insults via the modulation of abventricular divisions thereby ensuring the production of an appropriate number of neurons.


Subject(s)
Cell Proliferation/physiology , Cerebral Cortex/cytology , Cerebral Cortex/embryology , Neurons/cytology , Animals , Cell Death , Gene Expression Regulation, Developmental/physiology , Mice, Transgenic , Neural Stem Cells/cytology , Neurogenesis/physiology
10.
Development ; 141(2): 377-88, 2014 Jan.
Article in English | MEDLINE | ID: mdl-24335253

ABSTRACT

During embryonic development, the rostral neuroectoderm is regionalized into broad areas that are subsequently subdivided into progenitor compartments with specialized identity and fate. These events are controlled by signals emitted by organizing centers and interpreted by target progenitors, which activate superimposing waves of intrinsic factors restricting their identity and fate. The transcription factor Otx2 plays a crucial role in mesencephalic development by positioning the midbrain-hindbrain boundary (MHB) and its organizing activity. Here, we investigated whether Otx2 is cell-autonomously required to control identity and fate of dorsal mesencephalic progenitors. With this aim, we have inactivated Otx2 in the Pax7(+) dorsal mesencephalic domain, previously named m1, without affecting MHB integrity. We found that the Pax7(+) m1 domain can be further subdivided into a dorsal Zic1(+) m1a and a ventral Zic1(-) m1b sub-domain. Loss of Otx2 in the m1a (Pax7(+) Zic1(+)) sub-domain impairs the identity and fate of progenitors, which undergo a full switch into a coordinated cerebellum differentiation program. By contrast, in the m1b sub-domain (Pax7(+) Zic1(-)) Otx2 is prevalently required for post-mitotic transition of mesencephalic GABAergic precursors. Moreover, genetic cell fate, BrdU cell labeling and Otx2 conditional inactivation experiments indicate that in Otx2 mutants all ectopic cerebellar cell types, including external granule cell layer (EGL) precursors, originate from the m1a progenitor sub-domain and that reprogramming of mesencephalic precursors into EGL or cerebellar GABAergic progenitors depends on temporal sensitivity to Otx2 ablation. Together, these findings indicate that Otx2 intrinsically controls different aspects of dorsal mesencephalic neurogenesis. In this context, Otx2 is cell-autonomously required in the m1a sub-domain to suppress cerebellar fate and promote mesencephalic differentiation independently of the MHB organizing activity.


Subject(s)
Cerebellum/embryology , Cerebellum/metabolism , Mesencephalon/embryology , Mesencephalon/metabolism , Otx Transcription Factors/metabolism , Animals , Body Patterning , Cell Differentiation , Embryonic Stem Cells/cytology , Embryonic Stem Cells/metabolism , Female , Mice , Mice, Knockout , Mice, Mutant Strains , Mice, Transgenic , Mutation , Neural Stem Cells/cytology , Neural Stem Cells/metabolism , Neurogenesis , Organizers, Embryonic/embryology , Organizers, Embryonic/metabolism , Otx Transcription Factors/deficiency , Otx Transcription Factors/genetics , PAX7 Transcription Factor/metabolism , Pregnancy , Transcription Factors/deficiency , Transcription Factors/genetics , Transcription Factors/metabolism
11.
Cereb Cortex ; 25(10): 3446-57, 2015 Oct.
Article in English | MEDLINE | ID: mdl-25085881

ABSTRACT

Cajal-Retzius (CR) cells are essential for cortical development and lamination. These pioneer neurons arise from distinct progenitor sources, including the cortical hem and the ventral pallium at pallium-subpallium boundary (PSB). CXCR4, the canonical receptor for the chemokine CXCL12, controls the superficial location of hem-derived CR cells. However, recent studies showed that CXCR7, a second CXCL12 receptor, is also expressed in CR cells at early developmental stages. We thus investigated the role of CXCR7 during CR cell development using multiple loss-of-function approaches. Cxcr7 gene inactivation led to aberrant localization of Reelin-positive cells within the pallium. In addition, Cxcr7(-/-) mice were characterized by significant accumulation of ectopic CR cells in the lateral part of the dorsal pallium compared with Cxcr4 knockout mice. Loss-of-function approaches, using either gene targeting or pharmacological receptor inhibition, reveal that CXCR7 and CXCR4 act both in CR positioning. Finally, conditional Cxcr7 deletion in cells derived from Dbx1-expressing progenitors indicates an essential role of CXCR7 in controlling the positioning of a subpopulation of PSB-derived CR cells. Our data demonstrate that CXCR7 has a role in the positioning of hem and PSB-derived CR cells, CXCL12 regulating CR cell subpial localization through the combined action of CXCR4 and CXCR7.


Subject(s)
Cell Movement , Cerebral Cortex/embryology , Neurons/physiology , Receptors, CXCR/metabolism , Animals , Cell Adhesion Molecules, Neuronal/metabolism , Cerebral Cortex/cytology , Cerebral Cortex/metabolism , Extracellular Matrix Proteins/metabolism , Mice , Nerve Tissue Proteins/metabolism , Neurons/metabolism , Receptors, CXCR4/metabolism , Reelin Protein , Serine Endopeptidases/metabolism , Signal Transduction
12.
Cereb Cortex ; 24(5): 1361-72, 2014 May.
Article in English | MEDLINE | ID: mdl-23307637

ABSTRACT

Early brain development is regulated by the coordinated actions of multiple signaling centers at key boundaries between compartments. Three telencephalic midline structures are in a position to play such roles in forebrain patterning: The cortical hem, the septum, and the thalamic eminence at the diencephalic-telencephalic boundary. These structures express unique complements of signaling molecules, and they also produce distinct populations of Cajal-Retzius cells, which are thought to act as "mobile patterning units," migrating tangentially to cover the telencephalic surface. We show that these 3 structures require the transcription factor Lhx2 to delimit their extent. In the absence of Lhx2 function, all 3 structures are greatly expanded, and the Cajal-Retzius cell population is dramatically increased. We propose that the hem, septum, and thalamic eminence together form a "forebrain hem system" that defines and regulates the formation of the telencephalic midline. Disruptions in the forebrain hem system may be implicated in severe brain malformations such as holoprosencephaly. Lhx2 functions as a central regulator of this system's development. Since all components of the forebrain hem system have been identified across several vertebrate species, the mechanisms that regulate them may have played a fundamental role in driving key aspects of forebrain evolution.


Subject(s)
Gene Expression Regulation, Developmental/genetics , LIM-Homeodomain Proteins/metabolism , Neural Pathways/embryology , Neural Pathways/metabolism , Prosencephalon/embryology , Prosencephalon/metabolism , Transcription Factors/metabolism , Age Factors , Animals , Biological Evolution , Bromodeoxyuridine/metabolism , Cell Differentiation , Embryo, Mammalian , Fetus , Humans , Ki-67 Antigen/metabolism , LIM-Homeodomain Proteins/genetics , Mice , Mice, Transgenic , Models, Neurological , Mutation/genetics , Prosencephalon/cytology , Transcription Factors/genetics
13.
Cereb Cortex ; 24(6): 1409-21, 2014 Jun.
Article in English | MEDLINE | ID: mdl-23307639

ABSTRACT

To gain new insights into the transcriptional regulation of cortical development, we examined the role of the transcription factor Sp8, which is downstream of Fgf8 signaling and known to promote rostral cortical development. We have used a binary transgenic system to express Sp8 throughout the mouse telencephalon in a temporally restricted manner. Our results show that misexpression of Sp8 throughout the telencephalon, at early but not late embryonic stages, results in cortical hypoplasia, which is accompanied by increased cell death, reduced proliferation, and precocious neuronal differentiation. Misexpression of Sp8 at early developmental stages represses COUP-TF1 expression, a negative effector of Fgf signaling and a key promoter of posterior cortical identity, while ablation of Sp8 has the opposite effect. In addition, transgenic misexpression of COUP-TF1 resulted in downregulation of Sp8, indicating a reciprocal cross-regulation between these 2 transcription factors. Although Sp8 has been suggested to induce and/or maintain Fgf8 expression in the embryonic telencephalon, neither Fgf8 nor Fgf15 was upregulated using our gain-of-function approach. However, misexpression of Sp8 greatly increased the expression of Fgf target molecules, suggesting enhanced Fgf signaling. Thus, we propose that Sp8 promotes rostral and dorsomedial cortical development by repressing COUP-TF1 and promoting Fgf signaling in pallial progenitors.


Subject(s)
COUP Transcription Factor I/metabolism , Cerebral Cortex/embryology , DNA-Binding Proteins/metabolism , Fibroblast Growth Factors/metabolism , Neural Stem Cells/physiology , Telencephalon/embryology , Transcription Factors/metabolism , Animals , Body Patterning/physiology , COUP Transcription Factor I/genetics , Cell Death/physiology , Cell Proliferation/physiology , Cerebral Cortex/physiology , DNA-Binding Proteins/genetics , Fibroblast Growth Factor 8/metabolism , Globus Pallidus/embryology , Globus Pallidus/physiology , Mice, Transgenic , Models, Neurological , Neurogenesis/physiology , Signal Transduction/physiology , Telencephalon/physiology , Transcription Factors/genetics
14.
J Clin Invest ; 134(16)2024 Jul 09.
Article in English | MEDLINE | ID: mdl-38980724

ABSTRACT

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. We identified inherited and de novo RELN missense variants in heterozygous patients with neuronal migration disorders (NMDs) as diverse as pachygyria and polymicrogyria. We investigated in culture and in the developing mouse cerebral cortex how different variants impacted RELN function. Polymicrogyria-associated variants behaved as gain-of-function, showing an enhanced ability to induce neuronal aggregation, while those linked to pachygyria behaved as loss-of-function, leading to defective neuronal aggregation/migration. The pachygyria-associated de novo heterozygous RELN variants acted as dominant-negative by preventing WT RELN secretion in culture, animal models, and patients, thereby causing dominant NMDs. We demonstrated how mutant RELN proteins in vitro and in vivo predict cortical malformation phenotypes, providing valuable insights into the pathogenesis of such disorders.


Subject(s)
Cell Adhesion Molecules, Neuronal , Cell Movement , Extracellular Matrix Proteins , Mutation, Missense , Nerve Tissue Proteins , Reelin Protein , Serine Endopeptidases , Humans , Animals , Extracellular Matrix Proteins/genetics , Extracellular Matrix Proteins/metabolism , Serine Endopeptidases/genetics , Serine Endopeptidases/metabolism , Cell Adhesion Molecules, Neuronal/genetics , Cell Adhesion Molecules, Neuronal/metabolism , Nerve Tissue Proteins/genetics , Nerve Tissue Proteins/metabolism , Mice , Female , Male , Cell Movement/genetics , Neurons/metabolism , Neurons/pathology , Polymicrogyria/genetics , Polymicrogyria/pathology , Cerebral Cortex/metabolism , Cerebral Cortex/pathology , Heterozygote , Lissencephaly/genetics , Lissencephaly/pathology , Alleles
15.
Development ; 137(2): 293-302, 2010 Jan.
Article in English | MEDLINE | ID: mdl-20040495

ABSTRACT

Cajal-Retzius (CR) cells play a key role in the formation of the cerebral cortex. These pioneer neurons are distributed throughout the cortical marginal zone in distinct graded distributions. Fate mapping and cell lineage tracing studies have recently shown that CR cells arise from restricted domains of the pallial ventricular zone, which are associated with signalling centres involved in the early regionalisation of the telencephalic vesicles. In this study, we identified a subpopulation of CR cells in the rostral telencephalon that expresses Er81, a downstream target of Fgf8 signalling. We investigated the role of the rostral telencephalic patterning centre, which secretes FGF molecules, in the specification of these cells. Using pharmacological inhibitors and genetic inactivation of Fgf8, we showed that production of Fgf8 by the rostral telencephalic signalling centre is required for the specification of the Er81+ CR cell population. Moreover, the analysis of Fgf8 gain-of-function in cultivated mouse embryos and of Emx2 and Gli3 mutant embryos revealed that ectopic Fgf8 signalling promotes the generation of CR cells with a rostral phenotype from the dorsal pallium. These data showed that Fgf8 signalling is both required and sufficient to induce rostral CR cells. Together, our results shed light on the mechanisms specifying rostral CR cells and further emphasise the crucial role of telencephalic signalling centres in the generation of distinct CR cell populations.


Subject(s)
Fibroblast Growth Factor 8/metabolism , Signal Transduction , Animals , Cells, Cultured , Cerebral Cortex/embryology , Cerebral Cortex/metabolism , DNA-Binding Proteins/genetics , DNA-Binding Proteins/metabolism , Embryo, Mammalian/cytology , Embryo, Mammalian/metabolism , Fibroblast Growth Factor 8/genetics , Homeodomain Proteins/genetics , Homeodomain Proteins/metabolism , Immunohistochemistry , In Situ Hybridization , Kruppel-Like Transcription Factors/genetics , Kruppel-Like Transcription Factors/metabolism , Mice , Mice, Transgenic , Nerve Tissue Proteins/genetics , Nerve Tissue Proteins/metabolism , Telencephalon/cytology , Telencephalon/embryology , Transcription Factors/genetics , Transcription Factors/metabolism , Zinc Finger Protein Gli3
16.
PLoS Biol ; 8(7): e1000440, 2010 Jul 27.
Article in English | MEDLINE | ID: mdl-20668538

ABSTRACT

Patterning of the cortical neuroepithelium occurs at early stages of embryonic development in response to secreted molecules from signaling centers. These signals have been shown to establish the graded expression of transcription factors in progenitors within the ventricular zone and to control the size and positioning of cortical areas. Cajal-Retzius (CR) cells are among the earliest generated cortical neurons and migrate from the borders of the developing pallium to cover the cortical primordium by E11.5. We show that molecularly distinct CR subtypes distribute in specific combinations in pallial territories at the time of cortical regionalization. By means of genetic ablation experiments in mice, we report that loss of septum Dbx1-derived CR cells in the rostromedial pallium between E10.5 and E11.5 results in the redistribution of CR subtypes. This leads to changes in the expression of transcription factors within the neuroepithelium and in the proliferation properties of medial and dorsal cortical progenitors. Early regionalization defects correlate with shifts in the positioning of cortical areas at postnatal stages in the absence of alterations of gene expression at signaling centers. We show that septum-derived CR neurons express a highly specific repertoire of signaling factors. Our results strongly suggest that these cells, migrating over long distances and positioned in the postmitotic compartment, signal to ventricular zone progenitors and, thus, function as modulators of early cortical patterning.


Subject(s)
Body Patterning , Cerebral Cortex/cytology , Cerebral Cortex/embryology , Homeodomain Proteins/metabolism , Neuroepithelial Cells/cytology , Neuroepithelial Cells/metabolism , Animals , Body Patterning/genetics , Cell Proliferation , Cerebral Cortex/metabolism , Flow Cytometry , Gene Expression Profiling , Gene Expression Regulation, Developmental , Homeodomain Proteins/genetics , Mice , Neurogenesis , RNA, Messenger/genetics , RNA, Messenger/metabolism , Septum of Brain/cytology , Septum of Brain/embryology , Septum of Brain/metabolism , Wnt Proteins/metabolism
17.
PLoS Biol ; 8(6): e1000382, 2010 Jun 01.
Article in English | MEDLINE | ID: mdl-20532235

ABSTRACT

Morphogens are secreted signalling molecules that act in a graded manner to control the pattern of cellular differentiation in developing tissues. An example is Sonic hedgehog (Shh), which acts in several developing vertebrate tissues, including the central nervous system, to provide positional information during embryonic patterning. Here we address how Shh signalling assigns the positional identities of distinct neuronal subtype progenitors throughout the ventral neural tube. Assays of intracellular signal transduction and gene expression indicate that the duration as well as level of signalling is critical for morphogen interpretation. Progenitors of the ventral neuronal subtypes are established sequentially, with progressively more ventral identities requiring correspondingly higher levels and longer periods of Shh signalling. Moreover, cells remain sensitive to changes in Shh signalling for an extended time, reverting to antecedent identities if signalling levels fall below a threshold. Thus, the duration of signalling is important not only for the assignment but also for the refinement and maintenance of positional identity. Together the data suggest a dynamic model for ventral neural tube patterning in which positional information corresponds to the time integral of Shh signalling. This suggests an alternative to conventional models of morphogen action that rely solely on the level of signalling.


Subject(s)
Hedgehog Proteins/physiology , Neural Tube/embryology , Vertebrates/embryology , Animals , Hedgehog Proteins/metabolism , Signal Transduction
18.
Curr Opin Neurobiol ; 79: 102686, 2023 04.
Article in English | MEDLINE | ID: mdl-36774666

ABSTRACT

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. In this review, we present some of the findings that allow us to better appreciate the identity and diversity of this very special cell type, and propose a unified definition of what should be considered a Cajal-Retzius cell, especially when working with non-mammalian species or organoids. In addition, we highlight a flurry of recent studies pointing to the importance of CRs in the assembly of functional and dysfunctional cortical networks.


Subject(s)
Cerebral Cortex , Neurons , Humans , Neurons/physiology , Hippocampus/physiology
19.
J Comp Neurol ; 531(12): 1229-1243, 2023 08.
Article in English | MEDLINE | ID: mdl-37125418

ABSTRACT

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. We demonstrate that Dbx1 itself is dispensable for neuronal fate specification and global organization of the olfactory sensory system. Using lineage tracing, we characterize the contribution of Dbx1 lineages to OSN, VSN, and GnRH neuron populations and reveal an unexpected degree of diversity. Furthermore, we demonstrate that Dbx1-expressing progenitors remain neurogenic in the absence of the proneural gene Ascl1. Our work therefore points to the existence of distinct neurogenic programs in Dbx1-derived and other olfactory lineages.


Subject(s)
Olfactory Mucosa , Olfactory Receptor Neurons , Mice , Animals , Olfactory Receptor Neurons/metabolism , Transcription Factors/genetics , Gene Expression Regulation , Gonadotropin-Releasing Hormone/metabolism , Homeodomain Proteins/genetics
20.
Dev Cell ; 58(15): 1365-1382.e6, 2023 08 07.
Article in English | MEDLINE | ID: mdl-37321213

ABSTRACT

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. Upon deletion of Gmnc, the master regulator of multiciliogenesis, CRs are initially produced but fail to reach their normal identity resulting in their massive apoptosis. We further dissect the contribution of multiciliation effector genes and identify Trp73 as a key determinant. Finally, we use in utero electroporation to demonstrate that the intrinsic competence of hem progenitors as well as the heterochronic expression of Gmnc prevent centriole amplification in the CR lineage. Our work exemplifies how the co-option of a complete gene module, repurposed to control a distinct process, may contribute to the emergence of novel cell identities.


Subject(s)
Cerebral Cortex , Gene Regulatory Networks , Mice , Animals , Cerebral Cortex/metabolism , Neurons/metabolism , Cell Differentiation/physiology , Neurogenesis/genetics
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