RESUMO
Schwann cell precursors (SCPs) are nerve-associated progenitors that can generate myelinating and non-myelinating Schwann cells but also are multipotent like the neural crest cells from which they originate. SCPs are omnipresent along outgrowing peripheral nerves throughout the body of vertebrate embryos. By using single-cell transcriptomics to generate a gene expression atlas of the entire neural crest lineage, we show that early SCPs and late migratory crest cells have similar transcriptional profiles characterised by a multipotent "hub" state containing cells biased towards traditional neural crest fates. SCPs keep diverging from the neural crest after being primed towards terminal Schwann cells and other fates, with different subtypes residing in distinct anatomical locations. Functional experiments using CRISPR-Cas9 loss-of-function further show that knockout of the common "hub" gene Sox8 causes defects in neural crest-derived cells along peripheral nerves by facilitating differentiation of SCPs towards sympathoadrenal fates. Finally, specific tumour populations found in melanoma, neurofibroma and neuroblastoma map to different stages of SCP/Schwann cell development. Overall, SCPs resemble migrating neural crest cells that maintain multipotency and become transcriptionally primed towards distinct lineages.
Assuntos
Crista Neural , Células de Schwann , Diferenciação Celular/fisiologia , Neurogênese/fisiologia , Nervos Periféricos , Células de Schwann/metabolismoRESUMO
A wealth of specialized neuroendocrine command systems intercalated within the hypothalamus control the most fundamental physiological needs in vertebrates1,2. Nevertheless, we lack a developmental blueprint that integrates the molecular determinants of neuronal and glial diversity along temporal and spatial scales of hypothalamus development3. Here we combine single-cell RNA sequencing of 51,199 mouse cells of ectodermal origin, gene regulatory network (GRN) screens in conjunction with genome-wide association study-based disease phenotyping, and genetic lineage reconstruction to show that nine glial and thirty-three neuronal subtypes are generated by mid-gestation under the control of distinct GRNs. Combinatorial molecular codes that arise from neurotransmitters, neuropeptides and transcription factors are minimally required to decode the taxonomical hierarchy of hypothalamic neurons. The differentiation of γ-aminobutyric acid (GABA) and dopamine neurons, but not glutamate neurons, relies on quasi-stable intermediate states, with a pool of GABA progenitors giving rise to dopamine cells4. We found an unexpected abundance of chemotropic proliferation and guidance cues that are commonly implicated in dorsal (cortical) patterning5 in the hypothalamus. In particular, loss of SLIT-ROBO signalling impaired both the production and positioning of periventricular dopamine neurons. Overall, we identify molecular principles that shape the developmental architecture of the hypothalamus and show how neuronal heterogeneity is transformed into a multimodal neural unit to provide virtually infinite adaptive potential throughout life.
Assuntos
Regulação da Expressão Gênica no Desenvolvimento , Hipotálamo/citologia , Hipotálamo/embriologia , Morfogênese , Animais , Diferenciação Celular , Linhagem da Célula , Dopamina/metabolismo , Neurônios Dopaminérgicos/citologia , Neurônios Dopaminérgicos/metabolismo , Ectoderma/citologia , Ectoderma/metabolismo , Feminino , Neurônios GABAérgicos/citologia , Neurônios GABAérgicos/metabolismo , Redes Reguladoras de Genes , Estudo de Associação Genômica Ampla , Ácido Glutâmico/metabolismo , Hipotálamo/metabolismo , Masculino , Camundongos , Morfogênese/genética , Proteínas do Tecido Nervoso/metabolismo , Neuroglia/citologia , Neuroglia/metabolismo , Neuropeptídeos/metabolismo , Neurotransmissores/metabolismo , Receptores Imunológicos/metabolismo , Regulon/genética , Transdução de Sinais , Fatores de Transcrição/metabolismo , Ácido gama-Aminobutírico/metabolismo , Proteínas RoundaboutRESUMO
For a long time, neurogenic placodes and migratory neural crest cells were considered the immediate sources building neurons of peripheral nervous system. Recently, a number of discoveries revealed the existence of another progenitor type-a nerve-associated multipotent Schwann cell precursors (SCPs) building enteric and parasympathetic neurons as well as neuroendocrine chromaffin cells. SCPs are neural crest-derived and are similar to the crest cells by their markers and differentiation potential. Such similarities, but also considerable differences, raise many questions pertaining to the medical side, fundamental developmental biology and evolution. Here, we discuss the genesis of Schwann cell precursors, their role in building peripheral neural structures and ponder on their role in the origin in congenial diseases associated with peripheral nervous systems.
Assuntos
Neurogênese , Neurônios/citologia , Células de Schwann/citologia , Células-Tronco/citologia , Animais , Células Cromafins/citologia , Células Cromafins/metabolismo , Humanos , Neurônios/metabolismo , Sistema Nervoso Periférico/citologia , Sistema Nervoso Periférico/metabolismo , Células de Schwann/metabolismo , Células-Tronco/metabolismoRESUMO
Melanocytes are pigmented cells residing mostly in the skin and hair follicles of vertebrates, where they contribute to colouration and protection against UV-B radiation. However, the spectrum of their functions reaches far beyond that. For instance, these pigment-producing cells are found inside the inner ear, where they contribute to the hearing function, and in the heart, where they are involved in the electrical conductivity and support the stiffness of cardiac valves. The embryonic origin of such extracutaneous melanocytes is not clear. We took advantage of lineage-tracing experiments combined with 3D visualizations and gene knockout strategies to address this long-standing question. We revealed that Schwann cell precursors are recruited from the local innervation during embryonic development and give rise to extracutaneous melanocytes in the heart, brain meninges, inner ear, and other locations. In embryos with a knockout of the EdnrB receptor, a condition imitating Waardenburg syndrome, we observed only nerve-associated melanoblasts, which failed to detach from the nerves and to enter the inner ear. Finally, we looked into the evolutionary aspects of extracutaneous melanocytes and found that pigment cells are associated mainly with nerves and blood vessels in amphibians and fish. This new knowledge of the nerve-dependent origin of extracutaneous pigment cells might be directly relevant to the formation of extracutaneous melanoma in humans.
Assuntos
Encéfalo/fisiologia , Orelha Interna/fisiologia , Coração/fisiologia , Meninges/fisiologia , Sistema Nervoso/fisiopatologia , Células de Schwann/fisiologia , Anfíbios/metabolismo , Anfíbios/fisiologia , Animais , Encéfalo/metabolismo , Linhagem da Célula/fisiologia , Orelha Interna/metabolismo , Desenvolvimento Embrionário/fisiologia , Feminino , Peixes/metabolismo , Peixes/fisiologia , Melanócitos/metabolismo , Melanócitos/fisiologia , Meninges/metabolismo , Camundongos , Sistema Nervoso/metabolismo , Gravidez , Receptor de Endotelina B/metabolismo , Células de Schwann/metabolismoRESUMO
Immature multipotent embryonic peripheral glial cells, the Schwann cell precursors (SCPs), differentiate into melanocytes, parasympathetic neurons, chromaffin cells, and dental mesenchymal populations. Here, genetic lineage tracing revealed that, during murine embryonic development, some SCPs detach from nerve fibers to become mesenchymal cells, which differentiate further into chondrocytes and mature osteocytes. This occurred only during embryonic development, producing numerous craniofacial and trunk skeletal elements, without contributing to development of the appendicular skeleton. Formation of chondrocytes from SCPs also occurred in zebrafish, indicating evolutionary conservation. Our findings reveal multipotency of SCPs, providing a developmental link between the nervous system and skeleton.
Assuntos
Osso e Ossos/citologia , Linhagem da Célula/genética , Condrócitos/citologia , Células-Tronco Mesenquimais/citologia , Tecido Nervoso/citologia , Células de Schwann/citologia , Animais , Biomarcadores/metabolismo , Osso e Ossos/embriologia , Osso e Ossos/metabolismo , Diferenciação Celular , Condrócitos/metabolismo , Células Cromafins/citologia , Células Cromafins/metabolismo , Embrião de Mamíferos , Embrião não Mamífero , Desenvolvimento Embrionário , Expressão Gênica , Melanócitos/citologia , Melanócitos/metabolismo , Células-Tronco Mesenquimais/metabolismo , Camundongos , Células-Tronco Multipotentes/citologia , Células-Tronco Multipotentes/metabolismo , Proteína Proteolipídica de Mielina/genética , Proteína Proteolipídica de Mielina/metabolismo , Fibras Nervosas/metabolismo , Tecido Nervoso/embriologia , Tecido Nervoso/metabolismo , Crista Neural/citologia , Crista Neural/crescimento & desenvolvimento , Crista Neural/metabolismo , Células-Tronco Neurais/citologia , Células-Tronco Neurais/metabolismo , Neuroglia/citologia , Neuroglia/metabolismo , Neurônios/citologia , Neurônios/metabolismo , Osteócitos/citologia , Osteócitos/metabolismo , Fatores de Transcrição SOXE/genética , Fatores de Transcrição SOXE/metabolismo , Células de Schwann/metabolismo , Peixe-Zebra/embriologia , Peixe-Zebra/genética , Peixe-Zebra/metabolismoRESUMO
We have recently demonstrated that Sox10 -expressing ( Sox10 + ) cells give rise to mainly type-III neuronal taste bud cells that are responsible for sour and salt taste. The two tissue compartments containing Sox10 + cells in the surrounding of taste buds include the connective tissue core of taste papillae and von Ebner's glands (vEGs) that are connected to the trench of circumvallate and foliate papillae. In this study, we used inducible Cre mouse models to map the cell lineages of connective tissue (including stromal and Schwann cells) and vEGs and performed single cell RNA-sequencing of the epithelium of Sox10-Cre/tdT mouse circumvallate/vEG complex. In vivo lineage mapping showed that the distribution of traced cells in circumvallate taste buds was closely linked with that in the vEGs, but not in the connective tissue. Sox10 , but not the known stem cells marker Lgr5 , expression was enriched in the cell clusters of main ducts of vEGs that contained abundant proliferating cells, while Sox10-Cre/tdT expression was enriched in type-III taste bud cells and excretory ductal cells. Moreover, multiple genes encoding pathogen receptors are enriched in the vEG main ducts. Our data indicate that the main duct of vEGs is a source of Sox10 + taste bud progenitors and susceptible to pathogen infections.
RESUMO
The sympathetic nervous system controls bodily functions including vascular tone, cardiac rhythm, and the "fight-or-flight response". Sympathetic chain ganglia develop in parallel with preganglionic motor nerves extending from the neural tube, raising the question of whether axon targeting contributes to sympathetic chain formation. Using nerve-selective genetic ablations and lineage tracing in mouse, we reveal that motor nerve-associated Schwann cell precursors (SCPs) contribute sympathetic neurons and satellite glia after the initial seeding of sympathetic ganglia by neural crest. Motor nerve ablation causes mispositioning of SCP-derived sympathoblasts as well as sympathetic chain hypoplasia and fragmentation. Sympathetic neurons in motor-ablated embryos project precociously and abnormally towards dorsal root ganglia, eventually resulting in fusion of sympathetic and sensory ganglia. Cell interaction analysis identifies semaphorins as potential motor nerve-derived signaling molecules regulating sympathoblast positioning and outgrowth. Overall, central innervation functions both as infrastructure and regulatory niche to ensure the integrity of peripheral ganglia morphogenesis.
Assuntos
Gânglios Simpáticos , Neurônios Motores , Crista Neural , Células de Schwann , Sistema Nervoso Simpático , Animais , Sistema Nervoso Simpático/embriologia , Camundongos , Neurônios Motores/fisiologia , Células de Schwann/metabolismo , Crista Neural/citologia , Crista Neural/metabolismo , Gânglios Simpáticos/citologia , Gânglios Espinais , Semaforinas/metabolismo , Semaforinas/genética , Camundongos Transgênicos , Neuroglia/metabolismo , FemininoRESUMO
Parasites have evolved a variety of astonishing strategies to survive within their hosts, yet the most challenging event in their personal chronicles is the passage from one host to another. It becomes even more complex when a parasite needs to pass through the external environment. Therefore, the free-living stages of parasites present a wide range of adaptations for transmission. Parasitic flatworms from the group Digenea (flukes) have free-living larvae, cercariae, which are remarkably diverse in structure and behavior.1,2 One of the cercariae transmission strategies is to attain a prey-like appearance for the host.3 This can be done through the formation of a swimming aggregate of several cercariae adjoined together by their tails.4 Through the use of live observations and light, electron, and confocal microscopy, we described such a supposedly prey-mimetic colony comprising cercariae of two distinct morphotypes. They are functionally specialized: larger morphotype (sailors) enable motility, and smaller morphotype (passengers) presumably facilitate infection. The analysis of local read alignments between the two samples reveals that both cercaria types have identical 18S, 28S, and 5.8S rRNA genes. Further phylogenetic analysis of these ribosomal sequences indicates that our specimen belongs to the digenean family Acanthocolpidae, likely genus Pleorchis. This discovery provides a unique example and a novel insight into how morphologically and functionally heterogeneous individuals of the same species cooperate to build colonial organisms for the purpose of infection. This strategy bears resemblance to the cooperating castes of the same species found among insects.5.
Assuntos
Parasitos , Trematódeos , Humanos , Animais , Larva , Filogenia , Natação , Trematódeos/anatomia & histologia , Trematódeos/genética , Cercárias/anatomia & histologia , Cercárias/genéticaRESUMO
In addition to their roles in protecting nerves and increasing conduction velocity, peripheral glia plays key functions in blood vessel development by secreting molecules governing arteries alignment and maturation with nerves. Here, we show in mice that a specific, nerve-attached cell population, derived from boundary caps (BCs), constitutes a major source of mural cells for the developing skin vasculature. Using Cre-based reporter cell tracing and single-cell transcriptomics, we show that BC derivatives migrate into the skin along the nerves, detach from them, and differentiate into pericytes and vascular smooth muscle cells. Genetic ablation of this population affects the organization of the skin vascular network. Our results reveal the heterogeneity and extended potential of the BC population in mice, which gives rise to mural cells, in addition to previously described neurons, Schwann cells, and melanocytes. Finally, our results suggest that mural specification of BC derivatives takes place before their migration along nerves to the mouse skin.
Assuntos
Crista Neural , Tubo Neural , Camundongos , Animais , Crista Neural/fisiologia , Neuroglia , Células de Schwann , Pele , Diferenciação Celular/fisiologiaRESUMO
Genetic mutations accumulate in an organism's body throughout its lifetime. While somatic single-nucleotide variants have been well characterized in the human body, the patterns and consequences of large chromosomal alterations in normal tissues remain largely unknown. Here, we present a pan-tissue survey of mosaic chromosomal alterations (mCAs) in 948 healthy individuals from the Genotype-Tissue Expression project, augmenting RNA-based allelic imbalance estimation with haplotype phasing. We found that approximately a quarter of the individuals carry a clonally-expanded mCA in at least one tissue, with incidence strongly correlated with age. The prevalence and genome-wide patterns of mCAs vary considerably across tissue types, suggesting tissue-specific mutagenic exposure and selection pressures. The mCA landscapes in normal adrenal and pituitary glands resemble those in tumors arising from these tissues, whereas the same is not true for the esophagus and skin. Together, our findings show a widespread age-dependent emergence of mCAs across normal human tissues with intricate connections to tumorigenesis.
Assuntos
Aberrações Cromossômicas , Neoplasias , Humanos , Mutação , Neoplasias/genética , Desequilíbrio Alélico , EsôfagoRESUMO
A wealth of specialized cell populations within the skin facilitates its hair-producing, protective, sensory, and thermoregulatory functions. How the vast cell-type diversity and tissue architecture develops is largely unexplored. Here, with single-cell transcriptomics, spatial cell-type assignment, and cell-lineage tracing, we deconstruct early embryonic mouse skin during the key transitions from seemingly uniform developmental precursor states to a multilayered, multilineage epithelium, and complex dermal identity. We identify the spatiotemporal emergence of hair-follicle-inducing, muscle-supportive, and fascia-forming fibroblasts. We also demonstrate the formation of the panniculus carnosus muscle (PCM), sprouting blood vessels without pericyte coverage, and the earliest residence of mast and dendritic immune cells in skin. Finally, we identify an unexpected epithelial heterogeneity within the early single-layered epidermis and a signaling-rich periderm layer. Overall, this cellular and molecular blueprint of early skin development-which can be explored at https://kasperlab.org/tools-establishes histological landmarks and highlights unprecedented dynamic interactions among skin cells.
Assuntos
Epiderme , Pele , Camundongos , Animais , Folículo Piloso/patologia , Cabelo , EpitélioRESUMO
In this study we use comparative genomics to uncover a gene with uncharacterized function (1700011H14Rik/C14orf105/CCDC198), which we hereby name FAME (Factor Associated with Metabolism and Energy). We observe that FAME shows an unusually high evolutionary divergence in birds and mammals. Through the comparison of single nucleotide polymorphisms, we identify gene flow of FAME from Neandertals into modern humans. We conduct knockout experiments on animals and observe altered body weight and decreased energy expenditure in Fame knockout animals, corresponding to genome-wide association studies linking FAME with higher body mass index in humans. Gene expression and subcellular localization analyses reveal that FAME is a membrane-bound protein enriched in the kidneys. Although the gene knockout results in structurally normal kidneys, we detect higher albumin in urine and lowered ferritin in the blood. Through experimental validation, we confirm interactions between FAME and ferritin and show co-localization in vesicular and plasma membranes.
Assuntos
Metabolismo Energético , Estudo de Associação Genômica Ampla , Animais , Humanos , Peso Corporal , Metabolismo Energético/genética , Ferritinas/genética , Rim , Homem de NeandertalRESUMO
During embryonic development, nerve-associated Schwann cell precursors (SCPs) give rise to chromaffin cells of the adrenal gland via the "bridge" transient stage, according to recent functional experiments and single cell data from humans and mice. However, currently existing data do not resolve the finest heterogeneity of developing chromaffin populations. Here we took advantage of deep SmartSeq2 transcriptomic sequencing to expand our collection of individual cells from the developing murine sympatho-adrenal anlage and uncover the microheterogeneity of embryonic chromaffin cells and their corresponding developmental paths. We discovered that SCPs on the splachnic nerve show a high degree of microheterogeneity corresponding to early biases towards either Schwann or chromaffin terminal fates. Furthermore, we found that a post-"bridge" population of developing chromaffin cells gives rise to persisting oxygen-sensing chromaffin cells and the two terminal populations (adrenergic and noradrenergic) via diverging differentiation paths. Taken together, we provide a thorough identification of novel markers of adrenergic and noradrenergic populations in developing adrenal glands and report novel differentiation paths leading to them.
Assuntos
Células Cromafins , Glândulas Suprarrenais , Adrenérgicos , Animais , Diferenciação Celular/fisiologia , Feminino , Humanos , Camundongos , Norepinefrina , Oxigênio , GravidezRESUMO
Adrenal glands are the major organs releasing catecholamines and regulating our stress response. The mechanisms balancing generation of adrenergic chromaffin cells and protecting against neuroblastoma tumors are still enigmatic. Here we revealed that serotonin (5HT) controls the numbers of chromaffin cells by acting upon their immediate progenitor "bridge" cells via 5-hydroxytryptamine receptor 3A (HTR3A), and the aggressive HTR3Ahigh human neuroblastoma cell lines reduce proliferation in response to HTR3A-specific agonists. In embryos (in vivo), the physiological increase of 5HT caused a prolongation of the cell cycle in "bridge" progenitors leading to a smaller chromaffin population and changing the balance of hormones and behavioral patterns in adulthood. These behavioral effects and smaller adrenals were mirrored in the progeny of pregnant female mice subjected to experimental stress, suggesting a maternal-fetal link that controls developmental adaptations. Finally, these results corresponded to a size-distribution of adrenals found in wild rodents with different coping strategies.
Assuntos
Células Cromafins , Neuroblastoma , Glândulas Suprarrenais/metabolismo , Animais , Catecolaminas/metabolismo , Células Cromafins/metabolismo , Feminino , Camundongos , Neuroblastoma/metabolismo , Gravidez , Serotonina/metabolismoRESUMO
Toll-like receptor (TLR) 4 responds to a range of agonists in infection and injury, but is best known for the recognition of bacterial lipopolysaccharides (LPS). Assembly in heterologous receptor complexes as well as signaling through both MyD88 and TRIF adaptor proteins, as unmatched by other TLRs, could underlie its versatile response options, probably also in a cell type-dependent manner. We show that microglia, the CNS macrophages, react to diverse LPS variants, including smooth (S) and rough (R) LPS chemotypes, with cytokine/chemokine induction, MHC I expression and suppression of myelin phagocytosis. The TLR4 co-receptor CD14 was shown in peritoneal macrophages to be essential for S-LPS effects and the link of both S- and R-LPS to TRIF signaling. In contrast, cd14(-/-) microglia readily respond to S- and R-LPS, suggesting an a priori high(er) sensitivity to both chemotypes, while CD14 confers increased S- and R-LPS potencies and compensates for their differences. Importantly, CD14 controls the magnitude and shapes the profile of cyto/chemokine production, this influence being itself regulated by critical LPS concentrations. Comparing reactive phenotypes of microglia with deficiencies in CD14, MyD88 and TRIF (cd14(-/-), myd88(-/-), and trif(lps2)), we found that distinct signaling routes organize for individual functions in either concerted or non-redundant fashion and that CD14 has contributions beyond the link to TRIF. Modulation of response profiles by key cytokines finally reveals that the microglial TLR4 can differentiate between the class of LPS structures and a self-derived agonist, fibronectin. It thus proves as a sophisticated decision maker in infectious and non-infectious CNS challenges.
Assuntos
Proteínas Adaptadoras de Transporte Vesicular/fisiologia , Receptores de Lipopolissacarídeos/fisiologia , Lipopolissacarídeos/farmacologia , Microglia/fisiologia , Receptor 4 Toll-Like/fisiologia , Animais , Proteínas Aviárias/fisiologia , Células Cultivadas , Citocinas/fisiologia , Citometria de Fluxo , Receptores de Lipopolissacarídeos/imunologia , Macrófagos Peritoneais/imunologia , Macrófagos Peritoneais/fisiologia , Complexo Principal de Histocompatibilidade/imunologia , Complexo Principal de Histocompatibilidade/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Microglia/imunologia , Fagocitose/fisiologia , Receptor 4 Toll-Like/agonistasRESUMO
Characterization of the progression of cellular states during human embryogenesis can provide insights into the origin of pediatric diseases. We examined the transcriptional states of neural crest- and mesoderm-derived lineages differentiating into adrenal glands, kidneys, endothelium and hematopoietic tissue between post-conception weeks 6 and 14 of human development. Our results reveal transitions connecting the intermediate mesoderm and progenitors of organ primordia, the hematopoietic system and endothelial subtypes. Unexpectedly, by using a combination of single-cell transcriptomics and lineage tracing, we found that intra-adrenal sympathoblasts at that stage are directly derived from nerve-associated Schwann cell precursors, similarly to local chromaffin cells, whereas the majority of extra-adrenal sympathoblasts arise from the migratory neural crest. In humans, this process persists during several weeks of development within the large intra-adrenal ganglia-like structures, which may also serve as reservoirs of originating cells in neuroblastoma.
Assuntos
Linhagem da Célula , Embrião de Mamíferos/metabolismo , Neuroblastoma/embriologia , Neuroblastoma/genética , Análise de Célula Única , Sistema Simpático-Suprarrenal/embriologia , Transcriptoma/genética , Animais , Células Cromafins/metabolismo , Células Cromafins/patologia , Análise por Conglomerados , Desenvolvimento Embrionário , Regulação da Expressão Gênica no Desenvolvimento , Regulação Neoplásica da Expressão Gênica , Humanos , Lactente , Camundongos , Células-Tronco Neurais/metabolismo , Neuroblastoma/patologia , Células de Schwann/metabolismo , Células de Schwann/patologia , Microambiente TumoralRESUMO
The mammalian adrenal gland is composed of two main components; the catecholaminergic neural crest-derived medulla, found in the center of the gland, and the mesoderm-derived cortex producing steroidogenic hormones. The medulla is composed of neuroendocrine chromaffin cells with oxygen-sensing properties and is dependent on tissue interactions with the overlying cortex, both during development and in adulthood. Other relevant organs include the Zuckerkandl organ containing extra-adrenal chromaffin cells, and carotid oxygen-sensing bodies containing glomus cells. Chromaffin and glomus cells reveal a number of important similarities and are derived from the multipotent nerve-associated descendants of the neural crest, or Schwann cell precursors. Abnormalities in complex developmental processes during differentiation of nerve-associated and other progenitors into chromaffin and oxygen-sensing populations may result in different subtypes of paraganglioma, neuroblastoma and pheochromocytoma. Here, we summarize recent findings explaining the development of chromaffin and oxygen-sensing cells, as well as the potential mechanisms driving neuroendocrine tumor initiation.
Assuntos
Doenças das Glândulas Suprarrenais/etiologia , Medula Suprarrenal/fisiologia , Evolução Biológica , Células-Tronco/fisiologia , Doenças das Glândulas Suprarrenais/patologia , Medula Suprarrenal/patologia , Animais , Diferenciação Celular , Humanos , Crista Neural/citologia , Crista Neural/fisiologia , Células-Tronco/citologia , Células-Tronco/patologiaRESUMO
Somatic sensation is defined by the existence of a diversity of primary sensory neurons with unique biological features and response profiles to external and internal stimuli. However, there is no coherent picture about how this diversity of cell states is transcriptionally generated. Here, we use deep single cell analysis to resolve fate splits and molecular biasing processes during sensory neurogenesis in mice. Our results identify a complex series of successive and specific transcriptional changes in post-mitotic neurons that delineate hierarchical regulatory states leading to the generation of the main sensory neuron classes. In addition, our analysis identifies previously undetected early gene modules expressed long before fate determination although being clearly associated with defined sensory subtypes. Overall, the early diversity of sensory neurons is generated through successive bi-potential intermediates in which synchronization of relevant gene modules and concurrent repression of competing fate programs precede cell fate stabilization and final commitment.
Assuntos
Neurogênese/genética , Células Receptoras Sensoriais/citologia , Células Receptoras Sensoriais/fisiologia , Análise de Sequência de RNA/métodos , Análise de Célula Única/métodos , Animais , Diferenciação Celular , Subunidade alfa 3 de Fator de Ligação ao Core/genética , Modelos Animais de Doenças , Feminino , Regulação da Expressão Gênica no Desenvolvimento , Redes Reguladoras de Genes , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neurônios/fisiologia , Células-TroncoRESUMO
Understanding cell types and mechanisms of dental growth is essential for reconstruction and engineering of teeth. Therefore, we investigated cellular composition of growing and non-growing mouse and human teeth. As a result, we report an unappreciated cellular complexity of the continuously-growing mouse incisor, which suggests a coherent model of cell dynamics enabling unarrested growth. This model relies on spatially-restricted stem, progenitor and differentiated populations in the epithelial and mesenchymal compartments underlying the coordinated expansion of two major branches of pulpal cells and diverse epithelial subtypes. Further comparisons of human and mouse teeth yield both parallelisms and differences in tissue heterogeneity and highlight the specifics behind growing and non-growing modes. Despite being similar at a coarse level, mouse and human teeth reveal molecular differences and species-specific cell subtypes suggesting possible evolutionary divergence. Overall, here we provide an atlas of human and mouse teeth with a focus on growth and differentiation.
Assuntos
Diferenciação Celular , Células-Tronco/citologia , Dente/citologia , Dente/crescimento & desenvolvimento , Adolescente , Adulto , Animais , Diferenciação Celular/genética , Células Epiteliais , Feminino , Regulação da Expressão Gênica no Desenvolvimento , Heterogeneidade Genética , Humanos , Incisivo/citologia , Incisivo/crescimento & desenvolvimento , Masculino , Mesoderma/citologia , Mesoderma/crescimento & desenvolvimento , Mesoderma/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Modelos Animais , Dente Molar/citologia , Dente Molar/crescimento & desenvolvimento , Odontoblastos , Adulto JovemRESUMO
Corticothalamic axons express Contactin-2 (CNTN2/TAG-1), a neuronal recognition molecule of the immunoglobulin superfamily involved in neurogenesis, neurite outgrowth, and fasciculation. TAG-1, which is expressed transiently by cortical pyramidal neurons during embryonic development, has been shown to be fundamental for axonal recognition, cellular migration, and neuronal proliferation in the developing cortex. Although Tag-1 -/- mice do not exhibit any obvious defects in the corticofugal system, the role of TAG-1+ neurons during the development of the cortex remains elusive. We have generated a mouse model expressing EGFP under the Tag-1 promoter and encompassing the coding sequence of Diptheria Toxin subunit A (DTA) under quiescence with no effect on the expression of endogenous Tag-1. We show that while the line recapitulates the expression pattern of the molecule, it highlights an extended expression in the forebrain, including multiple axonal tracts and neuronal populations, both spatially and temporally. Crossing these mice to the Emx1-Cre strain, we ablated the vast majority of TAG-1+ cortical neurons. Among the observed defects were a significantly smaller cortex, a reduction of corticothalamic axons as well as callosal and commissural defects. Such defects are common in neurodevelopmental disorders, thus this mouse could serve as a useful model to study physiological and pathophysiological cortical development.