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1.
Ann Anat ; 245: 152017, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36280189

RESUMO

BACKGROUND: The mammalian tongue is a highly specialized muscular organ. The Wnt5a ligand regulates muscle development by mediating the activation of several noncanonical Wnt signaling pathways in a receptor context-dependent fashion. However, there is poor information on the expression and behavior of Wnt5a proteins during muscle development of the embryonic tongue. METHODS: The spatiotemporal distribution profiles of the Wnt5a ligand and its receptors, receptor tyrosine kinase-like orphan receptor 2 (Ror2), Frizzled2 (Fzd2), and Frizzled5 (Fzd5), in the developing tongue muscles of prenatal mice from embryonic day 12.5-18.5 were analyzed using immunofluorescence (IF) double staining of a target protein and desmin, a marker protein of myogenic cells. Immunolabeling images were subjected to digital detection analysis using the WinROOF 2018 version 4.19.0 image processing software when needed. RESULTS: IF signals of the Wnt5a ligand protein and its receptors Ror2 and Fzd2 were detected in developing myoblasts and myotubes of the embryonic tongue, but they were undetectable in mature myofibers equipped with sarcomere structures. Fzd2 expression was specific for desmin-positive developing muscle cells, whereas those of Ror2 and the Wnt5a ligand were widespread and nonselective for desmin-positive cells and that of Fzd5 was predominant in desmin-negative cells of the epithelium and subepithelial mesenchyme. CONCLUSION: Developing muscle cells but not mature myofibers of the mouse embryonic tongue express the Wnt5a ligand and its receptors Ror2 and Fzd2, which may mediate Wnt5a signaling in the development processes of tongue muscle fibers.


Assuntos
Desenvolvimento Muscular , Língua , Via de Sinalização Wnt , Animais , Feminino , Camundongos , Gravidez , Desmina/metabolismo , Ligantes , Músculos/embriologia , Receptores Órfãos Semelhantes a Receptor Tirosina Quinase/metabolismo , Língua/embriologia , Proteína Wnt-5a/metabolismo , Receptores Frizzled/metabolismo
2.
Science ; 378(6621): eabg3679, 2022 11 18.
Artigo em Inglês | MEDLINE | ID: mdl-36395225

RESUMO

The Hippo signaling pathway is widely considered a master regulator of organ growth because of the prominent overgrowth phenotypes caused by experimental manipulation of its activity. Contrary to this model, we show here that removing Hippo transcriptional output did not impair the ability of the mouse liver and Drosophila eyes to grow to their normal size. Moreover, the transcriptional activity of the Hippo pathway effectors Yap/Taz/Yki did not correlate with cell proliferation, and hyperactivation of these effectors induced gene expression programs that did not recapitulate normal development. Concordantly, a functional screen in Drosophila identified several Hippo pathway target genes that were required for ectopic overgrowth but not normal growth. Thus, Hippo signaling does not instruct normal growth, and the Hippo-induced overgrowth phenotypes are caused by the activation of abnormal genetic programs.


Assuntos
Drosophila melanogaster , Olho , Regulação da Expressão Gênica no Desenvolvimento , Via de Sinalização Hippo , Fígado , Transcrição Genética , Proteínas com Motivo de Ligação a PDZ com Coativador Transcricional , Proteínas de Sinalização YAP , Animais , Camundongos , Drosophila melanogaster/embriologia , Drosophila melanogaster/genética , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , Olho/embriologia , Via de Sinalização Hippo/genética , Fígado/embriologia , Tamanho do Órgão , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , Transativadores/genética , Proteínas com Motivo de Ligação a PDZ com Coativador Transcricional/metabolismo , Proteínas de Sinalização YAP/metabolismo
3.
Philos Trans R Soc Lond B Biol Sci ; 377(1865): 20210256, 2022 12 05.
Artigo em Inglês | MEDLINE | ID: mdl-36252209

RESUMO

Implantation of the conceptus into the uterus is absolutely essential for successful embryo development. In humans, our understanding of this process has remained rudimentary owing to the inaccessibility of early implantation stages. Non-human primates recapitulate many aspects of human embryo development and provide crucial insights into trophoblast development, uterine receptivity and embryo invasion. Moreover, primate species exhibit a variety of implantation strategies and differ in embryo invasion depths. This review examines conservation and divergence of the key processes required for embryo implantation in different primates and in comparison with the canonical rodent model. We discuss trophectoderm compartmentalization, endometrial remodelling and embryo adhesion and invasion. Finally, we propose that studying the mechanism controlling invasion depth between different primate species may provide new insights and treatment strategies for placentation disorders in humans. This article is part of the theme issue 'Extraembryonic tissues: exploring concepts, definitions and functions across the animal kingdom'.


Assuntos
Implantação do Embrião , Primatas , Animais , Feminino , Gravidez , Endométrio/embriologia , Primatas/embriologia , Trofoblastos , Útero , Humanos
4.
Development ; 149(21)2022 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-36196625

RESUMO

Migration of myoblasts derived from the occipital somites is essential for tongue morphogenesis. However, the molecular mechanisms of myoblast migration remain elusive. In this study, we report that deletion of Isl1 in the mouse mandibular epithelium leads to aglossia due to myoblast migration defects. Isl1 regulates the expression pattern of chemokine ligand 12 (Cxcl12) in the first branchial arch through the Shh/Wnt5a cascade. Cxcl12+ mesenchymal cells in Isl1ShhCre embryos were unable to migrate to the distal region, but instead clustered in a relatively small proximal domain of the mandible. CXCL12 serves as a bidirectional cue for myoblasts expressing its receptor CXCR4 in a concentration-dependent manner, attracting Cxcr4+ myoblast invasion at low concentrations but repelling at high concentrations. The accumulation of Cxcl12+ mesenchymal cells resulted in high local concentrations of CXCL12, which prevented Cxcr4+ myoblast invasion. Furthermore, transgenic activation of Ihh alleviated defects in tongue development and rescued myoblast migration, confirming the functional involvement of Hedgehog signaling in tongue development. In summary, this study provides the first line of genetic evidence that the ISL1/SHH/CXCL12 axis regulates myoblast migration during tongue development.


Assuntos
Quimiocina CXCL12 , Proteínas Hedgehog , Proteínas com Homeodomínio LIM , Transdução de Sinais , Língua , Fatores de Transcrição , Animais , Camundongos , Movimento Celular/genética , Proteínas Hedgehog/genética , Proteínas Hedgehog/metabolismo , Ligantes , Transdução de Sinais/genética , Língua/embriologia , Proteínas com Homeodomínio LIM/genética , Fatores de Transcrição/genética , Quimiocina CXCL12/genética
5.
Eur Rev Med Pharmacol Sci ; 26(17): 6273-6282, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-36111928

RESUMO

OBJECTIVE: L1  cell adhesion molecule (L1CAM) is a glycoprotein characterized by three components: an extracellular region, a transmembrane segment, and a cytoplasmic tail. L1CAM is expressed in multiple human cells, including neurons. The neural cell adhesion molecule L1 has been implicated in a variety of neurologic processes, including neuritogenesis and cerebellar cell migration. The presence of L1CAM on the surface of nerve cells allows the adhesion of neurons among them. Furthermore, when it is bound to itself or to other proteins, L1-CAM induces signals inside the cell. The aim of this work was to study L1CAM expression in the human spinal cord during development, at different gestational ages, through immunohistochemistry. MATERIALS AND METHODS: Immunohistochemical analysis for L1CAM was performed in five human spinal cord samples, including three embryos and two fetuses of different gestational ages, ranging from 8 to 12 weeks. RESULTS: L1CAM expression was detected in all 5 spinal cords examined in this study. The adhesion molecule was found in the vast majority of cells. The highest levels of immunoreactivity for L1CAM were detected at the periphery of the developing organs, in the spinal cord zones occupied by sensory and motor fibers. In the alar and basal columns, immunoreactivity for L1CAM was characterized by a reticular pattern, being mainly expressed in axons. Strong reactivity of L1CAM was also found in extracellular vesicles. This extracellular localization might indicate the ability of L1CAM to mediate the transduction of extracellular signals that support axon outgrowth. CONCLUSIONS: The high reactivity of L1cam in the axons of developing neurons in the fetal spinal cord confirms previous studies on the ability of L1CAM to promote axon sprouting and branching in the developing nervous system. In this work, a new actor is reported to have a role in the complex field of human spinal cord development: L1CAM, whose expression is highly found in the developing neuronal and glial precursors.


Assuntos
Vesículas Extracelulares , Molécula L1 de Adesão de Célula Nervosa , Medula Espinal , Axônios/metabolismo , Embrião de Mamíferos , Vesículas Extracelulares/metabolismo , Humanos , Lactente , Molécula L1 de Adesão de Célula Nervosa/genética , Molécula L1 de Adesão de Célula Nervosa/metabolismo , Medula Espinal/embriologia , Medula Espinal/crescimento & desenvolvimento , Medula Espinal/metabolismo
6.
Science ; 377(6611): 1155-1156, 2022 09 09.
Artigo em Inglês | MEDLINE | ID: mdl-36074827

RESUMO

A genetic change could explain increased cortical neurogenesis in modern humans.


Assuntos
Evolução Biológica , Neocórtex , Neurogênese , Neurônios , Animais , Humanos , Neocórtex/citologia , Neocórtex/embriologia , Neurogênese/genética , Neurônios/citologia
7.
Science ; 377(6613): eabl3921, 2022 09 23.
Artigo em Inglês | MEDLINE | ID: mdl-36137018

RESUMO

The vertebrate intestine forms by asymmetric gut rotation and elongation, and errors cause lethal obstructions in human infants. Rotation begins with tissue deformation of the dorsal mesentery, which is dependent on left-sided expression of the Paired-like transcription factor Pitx2. The conserved morphogen Nodal induces asymmetric Pitx2 to govern embryonic laterality, but organ-level regulation of Pitx2 during gut asymmetry remains unknown. We found Nodal to be dispensable for Pitx2 expression during mesentery deformation. Intestinal rotation instead required a mechanosensitive latent transforming growth factor-ß (TGFß), tuning a second wave of Pitx2 that induced reciprocal tissue stiffness in the left mesentery as mechanical feedback with the right side. This signaling regulator, an accelerator (right) and brake (left), combines biochemical and biomechanical inputs to break gut morphological symmetry and direct intestinal rotation.


Assuntos
Gastrulação , Regulação da Expressão Gênica no Desenvolvimento , Proteínas de Homeodomínio , Intestinos , Mecanotransdução Celular , Proteína Nodal , Fatores de Transcrição , Fator de Crescimento Transformador beta , Animais , Embrião de Galinha , Gastrulação/genética , Gastrulação/fisiologia , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/farmacologia , Intestinos/embriologia , Mecanotransdução Celular/genética , Mecanotransdução Celular/fisiologia , Camundongos , Proteína Nodal/genética , Fatores de Transcrição/genética , Fatores de Transcrição/farmacologia , Fator de Crescimento Transformador beta/metabolismo
9.
Science ; 377(6613): eabq5011, 2022 09 23.
Artigo em Inglês | MEDLINE | ID: mdl-36137051

RESUMO

Recent evidence has shown that even mild mutations in the Huntingtin gene that are associated with late-onset Huntington's disease (HD) disrupt various aspects of human neurodevelopment. To determine whether these seemingly subtle early defects affect adult neural function, we investigated neural circuit physiology in newborn HD mice. During the first postnatal week, HD mice have less cortical layer 2/3 excitatory synaptic activity than wild-type mice, express fewer glutamatergic receptors, and show sensorimotor deficits. The circuit self-normalizes in the second postnatal week but the mice nonetheless develop HD. Pharmacologically enhancing glutamatergic transmission during the neonatal period, however, rescues these deficits and preserves sensorimotor function, cognition, and spine and synapse density as well as brain region volume in HD adult mice.


Assuntos
Encéfalo , Proteína Huntingtina , Doença de Huntington , Rede Nervosa , Neurogênese , Sinapses , Animais , Encéfalo/anormalidades , Modelos Animais de Doenças , Humanos , Proteína Huntingtina/genética , Doença de Huntington/embriologia , Doença de Huntington/genética , Camundongos , Camundongos Transgênicos , Rede Nervosa/anormalidades , Neurogênese/genética , Sinapses/fisiologia
10.
Proc Natl Acad Sci U S A ; 119(37): e2208465119, 2022 09 13.
Artigo em Inglês | MEDLINE | ID: mdl-36067310

RESUMO

Gene expression is tightly regulated by RNA-binding proteins (RBPs) to facilitate cell survival, differentiation, and migration. Previous reports have shown the importance of the Insulin-like Growth Factor II mRNA-Binding Protein (IGF2BP1/IMP1/ZBP1) in regulating RNA fate, including localization, transport, and translation. Here, we generated and characterized a knockout mouse to study RBP regulation. We report that IGF2BP1 is essential for proper brain development and neonatal survival. Specifically, these mice display disorganization in the developing neocortex, and further investigation revealed a loss of cortical marginal cell density at E17.5. We also investigated migratory cell populations in the IGF2BP1[Formula: see text] mice, using BrdU labeling, and detected fewer mitotically active cells in the cortical plate. Since RNA localization is important for cellular migration and directionality, we investigated the regulation of ß-actin messenger RNA (mRNA), a well-characterized target with established roles in cell motility and development. To aid in our understanding of RBP and target mRNA regulation, we generated mice with endogenously labeled ß-actin mRNA (IGF2BP1[Formula: see text]; ß-actin-MS2[Formula: see text]). Using endogenously labeled ß-actin transcripts, we report IGF2BP1[Formula: see text] neurons have increased transcription rates and total ß-actin protein content. In addition, we found decreased transport and anchoring in knockout neurons. Overall, we present an important model for understanding RBP regulation of target mRNA.


Assuntos
Actinas , Encéfalo , Proteínas de Ligação a RNA , Actinas/genética , Actinas/metabolismo , Animais , Encéfalo/embriologia , Encéfalo/metabolismo , Movimento Celular/genética , Camundongos , Camundongos Knockout , Neurônios/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/metabolismo
11.
Proc Natl Acad Sci U S A ; 119(37): e2120079119, 2022 09 13.
Artigo em Inglês | MEDLINE | ID: mdl-36067316

RESUMO

The extracellular protein Reelin, expressed by Cajal-Retzius (CR) cells at early stages of cortical development and at late stages by GABAergic interneurons, regulates radial migration and the "inside-out" pattern of positioning. Current models of Reelin functions in corticogenesis focus on early CR cell-derived Reelin in layer I. However, developmental disorders linked to Reelin deficits, such as schizophrenia and autism, are related to GABAergic interneuron-derived Reelin, although its role in migration has not been established. Here we selectively inactivated the Reln gene in CR cells or GABAergic interneurons. We show that CR cells have a major role in the inside-out order of migration, while CR and GABAergic cells sequentially cooperate to prevent invasion of cortical neurons into layer I. Furthermore, GABAergic cell-derived Reelin compensates some features of the reeler phenotype and is needed for the fine tuning of the layer-specific distribution of cortical neurons. In the hippocampus, the inactivation of Reelin in CR cells causes dramatic alterations in the dentate gyrus and mild defects in the hippocampus proper. These findings lead to a model in which both CR and GABAergic cell-derived Reelin cooperate to build the inside-out order of corticogenesis, which might provide a better understanding of the mechanisms involved in the pathogenesis of neuropsychiatric disorders linked to abnormal migration and Reelin deficits.


Assuntos
Córtex Cerebral , Proteínas do Tecido Nervoso , Neurônios , Proteína Reelina , Animais , Movimento Celular , Córtex Cerebral/citologia , Córtex Cerebral/embriologia , Neurônios GABAérgicos/enzimologia , Hipocampo/embriologia , Hipocampo/enzimologia , Interneurônios/enzimologia , Camundongos , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Neurônios/citologia , Neurônios/enzimologia , Proteína Reelina/genética , Proteína Reelina/metabolismo
12.
Proc Natl Acad Sci U S A ; 119(37): e2207433119, 2022 09 13.
Artigo em Inglês | MEDLINE | ID: mdl-36074819

RESUMO

A cardinal feature of the auditory pathway is frequency selectivity, represented in a tonotopic map from the cochlea to the cortex. The molecular determinants of the auditory frequency map are unknown. Here, we discovered that the transcription factor ISL1 regulates the molecular and cellular features of auditory neurons, including the formation of the spiral ganglion and peripheral and central processes that shape the tonotopic representation of the auditory map. We selectively knocked out Isl1 in auditory neurons using Neurod1Cre strategies. In the absence of Isl1, spiral ganglion neurons migrate into the central cochlea and beyond, and the cochlear wiring is profoundly reduced and disrupted. The central axons of Isl1 mutants lose their topographic projections and segregation at the cochlear nucleus. Transcriptome analysis of spiral ganglion neurons shows that Isl1 regulates neurogenesis, axonogenesis, migration, neurotransmission-related machinery, and synaptic communication patterns. We show that peripheral disorganization in the cochlea affects the physiological properties of hearing in the midbrain and auditory behavior. Surprisingly, auditory processing features are preserved despite the significant hearing impairment, revealing central auditory pathway resilience and plasticity in Isl1 mutant mice. Mutant mice have a reduced acoustic startle reflex, altered prepulse inhibition, and characteristics of compensatory neural hyperactivity centrally. Our findings show that ISL1 is one of the obligatory factors required to sculpt auditory structural and functional tonotopic maps. Still, upon Isl1 deletion, the ensuing central plasticity of the auditory pathway does not suffice to overcome developmentally induced peripheral dysfunction of the cochlea.


Assuntos
Vias Auditivas , Núcleo Coclear , Células Ciliadas Auditivas , Proteínas com Homeodomínio LIM , Neurogênese , Gânglio Espiral da Cóclea , Fatores de Transcrição , Animais , Vias Auditivas/embriologia , Cóclea/embriologia , Cóclea/inervação , Núcleo Coclear/embriologia , Células Ciliadas Auditivas/fisiologia , Proteínas com Homeodomínio LIM/genética , Proteínas com Homeodomínio LIM/fisiologia , Camundongos , Neurogênese/genética , Gânglio Espiral da Cóclea/enzimologia , Fatores de Transcrição/genética , Fatores de Transcrição/fisiologia
13.
Proc Natl Acad Sci U S A ; 119(38): e2206147119, 2022 09 20.
Artigo em Inglês | MEDLINE | ID: mdl-36095192

RESUMO

The neocortex, the center for higher brain function, first emerged in mammals and has become massively expanded and folded in humans, constituting almost half the volume of the human brain. Primary microcephaly, a developmental disorder in which the brain is smaller than normal at birth, results mainly from there being fewer neurons in the neocortex because of defects in neural progenitor cells (NPCs). Outer radial glia (oRGs), NPCs that are abundant in gyrencephalic species but rare in lissencephalic species, are thought to play key roles in the expansion and folding of the neocortex. However, how oRGs expand, whether they are necessary for neocortical folding, and whether defects in oRGs cause microcephaly remain important questions in the study of brain development, evolution, and disease. Here, we show that oRG expansion in mice, ferrets, and human cerebral organoids requires cyclin-dependent kinase 6 (CDK6), the mutation of which causes primary microcephaly via an unknown mechanism. In a mouse model in which increased Hedgehog signaling expands oRGs and intermediate progenitor cells and induces neocortical folding, CDK6 loss selectively decreased oRGs and abolished neocortical folding. Remarkably, this function of CDK6 in oRG expansion did not require its kinase activity, was not shared by the highly similar CDK4 and CDK2, and was disrupted by the mutation causing microcephaly. Therefore, our results indicate that CDK6 is conserved to promote oRG expansion, that oRGs are necessary for neocortical folding, and that defects in oRG expansion may cause primary microcephaly.


Assuntos
Quinase 6 Dependente de Ciclina , Células Ependimogliais , Microcefalia , Neocórtex , Animais , Quinase 6 Dependente de Ciclina/genética , Quinase 6 Dependente de Ciclina/metabolismo , Células Ependimogliais/citologia , Células Ependimogliais/enzimologia , Furões , Proteínas Hedgehog/metabolismo , Humanos , Camundongos , Microcefalia/genética , Neocórtex/anormalidades , Neocórtex/enzimologia , Células-Tronco Neurais/citologia , Células-Tronco Neurais/enzimologia , Organoides/embriologia
14.
Nature ; 610(7930): 190-198, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-36131018

RESUMO

Although melanoma is notorious for its high degree of heterogeneity and plasticity1,2, the origin and magnitude of cell-state diversity remains poorly understood. Equally, it is unclear whether growth and metastatic dissemination are supported by overlapping or distinct melanoma subpopulations. Here, by combining mouse genetics, single-cell and spatial transcriptomics, lineage tracing and quantitative modelling, we provide evidence of a hierarchical model of tumour growth that mirrors the cellular and molecular logic underlying the cell-fate specification and differentiation of the embryonic neural crest. We show that tumorigenic competence is associated with a spatially localized perivascular niche, a phenotype acquired through an intercellular communication pathway established by endothelial cells. Consistent with a model in which only a fraction of cells are fated to fuel growth, temporal single-cell tracing of a population of melanoma cells with a mesenchymal-like state revealed that these cells do not contribute to primary tumour growth but, instead, constitute a pool of metastatic initiating cells that switch cell identity while disseminating to secondary organs. Our data provide a spatially and temporally resolved map of the diversity and trajectories of melanoma cell states and suggest that the ability to support growth and metastasis are limited to distinct pools of cells. The observation that these phenotypic competencies can be dynamically acquired after exposure to specific niche signals warrant the development of therapeutic strategies that interfere with the cancer cell reprogramming activity of such microenvironmental cues.


Assuntos
Proliferação de Células , Melanoma , Metástase Neoplásica , Animais , Comunicação Celular , Diferenciação Celular , Linhagem da Célula , Rastreamento de Células , Reprogramação Celular , Células Endoteliais , Melanoma/genética , Melanoma/patologia , Mesoderma/patologia , Camundongos , Metástase Neoplásica/patologia , Crista Neural/embriologia , Fenótipo , Análise de Célula Única , Transcriptoma , Microambiente Tumoral
15.
EMBO J ; 41(21): e111338, 2022 Nov 02.
Artigo em Inglês | MEDLINE | ID: mdl-36121125

RESUMO

The balance between self-renewal and differentiation in human foetal lung epithelial progenitors controls the size and function of the adult organ. Moreover, progenitor cell gene regulation networks are employed by both regenerating and malignant lung cells, where modulators of their effects could potentially be of therapeutic value. Details of the molecular networks controlling human lung progenitor self-renewal remain unknown. We performed the first CRISPRi screen in primary human lung organoids to identify transcription factors controlling progenitor self-renewal. We show that SOX9 promotes proliferation of lung progenitors and inhibits precocious airway differentiation. Moreover, by identifying direct transcriptional targets using Targeted DamID, we place SOX9 at the centre of a transcriptional network, which amplifies WNT and RTK signalling to stabilise the progenitor cell state. In addition, the proof-of-principle CRISPRi screen and Targeted DamID tools establish a new workflow for using primary human organoids to elucidate detailed functional mechanisms underlying normal development and disease.


Assuntos
Pulmão , Fatores de Transcrição SOX9 , Células-Tronco , Humanos , Diferenciação Celular/fisiologia , Pulmão/embriologia , Transdução de Sinais , Fatores de Transcrição SOX9/metabolismo , Células-Tronco/metabolismo
16.
Nature ; 609(7929): 1012-1020, 2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-36131015

RESUMO

Medulloblastoma, a malignant childhood cerebellar tumour, segregates molecularly into biologically distinct subgroups, suggesting that a personalized approach to therapy would be beneficial1. Mouse modelling and cross-species genomics have provided increasing evidence of discrete, subgroup-specific developmental origins2. However, the anatomical and cellular complexity of developing human tissues3-particularly within the rhombic lip germinal zone, which produces all glutamatergic neuronal lineages before internalization into the cerebellar nodulus-makes it difficult to validate previous inferences that were derived from studies in mice. Here we use multi-omics to resolve the origins of medulloblastoma subgroups in the developing human cerebellum. Molecular signatures encoded within a human rhombic-lip-derived lineage trajectory aligned with photoreceptor and unipolar brush cell expression profiles that are maintained in group 3 and group 4 medulloblastoma, suggesting a convergent basis. A systematic diagnostic-imaging review of a prospective institutional cohort localized the putative anatomical origins of group 3 and group 4 tumours to the nodulus. Our results connect the molecular and phenotypic features of clinically challenging medulloblastoma subgroups to their unified beginnings in the rhombic lip in the early stages of human development.


Assuntos
Linhagem da Célula , Neoplasias Cerebelares , Meduloblastoma , Metencéfalo , Animais , Neoplasias Cerebelares/classificação , Neoplasias Cerebelares/embriologia , Neoplasias Cerebelares/patologia , Cerebelo/embriologia , Humanos , Meduloblastoma/classificação , Meduloblastoma/embriologia , Meduloblastoma/patologia , Metencéfalo/embriologia , Camundongos , Neurônios/patologia , Estudos Prospectivos
17.
Nature ; 609(7929): 1021-1028, 2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-36131014

RESUMO

Medulloblastoma (MB) comprises a group of heterogeneous paediatric embryonal neoplasms of the hindbrain with strong links to early development of the hindbrain1-4. Mutations that activate Sonic hedgehog signalling lead to Sonic hedgehog MB in the upper rhombic lip (RL) granule cell lineage5-8. By contrast, mutations that activate WNT signalling lead to WNT MB in the lower RL9,10. However, little is known about the more commonly occurring group 4 (G4) MB, which is thought to arise in the unipolar brush cell lineage3,4. Here we demonstrate that somatic mutations that cause G4 MB converge on the core binding factor alpha (CBFA) complex and mutually exclusive alterations that affect CBFA2T2, CBFA2T3, PRDM6, UTX and OTX2. CBFA2T2 is expressed early in the progenitor cells of the cerebellar RL subventricular zone in Homo sapiens, and G4 MB transcriptionally resembles these progenitors but are stalled in developmental time. Knockdown of OTX2 in model systems relieves this differentiation blockade, which allows MB cells to spontaneously proceed along normal developmental differentiation trajectories. The specific nature of the split human RL, which is destined to generate most of the neurons in the human brain, and its high level of susceptible EOMES+KI67+ unipolar brush cell progenitor cells probably predisposes our species to the development of G4 MB.


Assuntos
Diferenciação Celular , Neoplasias Cerebelares , Meduloblastoma , Metencéfalo , Diferenciação Celular/genética , Linhagem da Célula , Neoplasias Cerebelares/classificação , Neoplasias Cerebelares/genética , Neoplasias Cerebelares/patologia , Cerebelo/embriologia , Cerebelo/patologia , Subunidades alfa de Fatores de Ligação ao Core/genética , Proteínas Hedgehog/metabolismo , Histona Desmetilases , Humanos , Antígeno Ki-67/metabolismo , Meduloblastoma/classificação , Meduloblastoma/genética , Meduloblastoma/patologia , Metencéfalo/embriologia , Metencéfalo/patologia , Proteínas Musculares , Mutação , Fatores de Transcrição Otx/deficiência , Fatores de Transcrição Otx/genética , Proteínas Repressoras , Proteínas com Domínio T/metabolismo , Fatores de Transcrição
18.
Nature ; 609(7929): 986-993, 2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-36104568

RESUMO

Nutrients and energy have emerged as central modulators of developmental programmes in plants and animals1-3. The evolutionarily conserved target of rapamycin (TOR) kinase is a master integrator of nutrient and energy signalling that controls growth. Despite its key regulatory roles in translation, proliferation, metabolism and autophagy2-5, little is known about how TOR shapes developmental transitions and differentiation. Here we show that glucose-activated TOR kinase controls genome-wide histone H3 trimethylation at K27 (H3K27me3) in Arabidopsis thaliana, which regulates cell fate and development6-10. We identify FERTILIZATION-INDEPENDENT ENDOSPERM (FIE), an indispensable component of Polycomb repressive complex 2 (PRC2), which catalyses H3K27me3 (refs. 6-8,10-12), as a TOR target. Direct phosphorylation by TOR promotes the dynamic translocation of FIE from the cytoplasm to the nucleus. Mutation of the phosphorylation site on FIE abrogates the global H3K27me3 landscape, reprogrammes the transcriptome and disrupts organogenesis in plants. Moreover, glucose-TOR-FIE-PRC2 signalling modulates vernalization-induced floral transition. We propose that this signalling axis serves as a nutritional checkpoint leading to epigenetic silencing of key transcription factor genes that specify stem cell destiny in shoot and root meristems and control leaf, flower and silique patterning, branching and vegetative-to-reproduction transition. Our findings reveal a fundamental mechanism of nutrient signalling in direct epigenome reprogramming, with broad relevance for the developmental control of multicellular organisms.


Assuntos
Arabidopsis , Glucose , Alvo Mecanístico do Complexo 2 de Rapamicina , Fosfatidilinositol 3-Quinases , Desenvolvimento Vegetal , Complexo Repressor Polycomb 2 , Proteínas Repressoras , Transdução de Sinais , Arabidopsis/embriologia , Arabidopsis/enzimologia , Arabidopsis/genética , Arabidopsis/metabolismo , Diferenciação Celular/genética , Linhagem da Célula/genética , Regulação da Expressão Gênica de Plantas , Inativação Gênica , Glucose/metabolismo , Histonas/química , Histonas/metabolismo , Alvo Mecanístico do Complexo 2 de Rapamicina/metabolismo , Mutação , Fosfatidilinositol 3-Quinases/metabolismo , Fosforilação , Desenvolvimento Vegetal/genética , Complexo Repressor Polycomb 2/metabolismo , Proteínas Repressoras/genética , Proteínas Repressoras/metabolismo , Fatores de Transcrição/genética
19.
Science ; 377(6611): eabl6422, 2022 09 09.
Artigo em Inglês | MEDLINE | ID: mdl-36074851

RESUMO

Neanderthal brains were similar in size to those of modern humans. We sought to investigate potential differences in neurogenesis during neocortex development. Modern human transketolase-like 1 (TKTL1) differs from Neanderthal TKTL1 by a lysine-to-arginine amino acid substitution. Using overexpression in developing mouse and ferret neocortex, knockout in fetal human neocortical tissue, and genome-edited cerebral organoids, we found that the modern human variant, hTKTL1, but not the Neanderthal variant, increases the abundance of basal radial glia (bRG) but not that of intermediate progenitors (bIPs). bRG generate more neocortical neurons than bIPs. The hTKTL1 effect requires the pentose phosphate pathway and fatty acid synthesis. Inhibition of these metabolic pathways reduces bRG abundance in fetal human neocortical tissue. Our data suggest that neocortical neurogenesis in modern humans differs from that in Neanderthals.


Assuntos
Homem de Neandertal , Neocórtex , Neurogênese , Transcetolase , Animais , Células Ependimogliais/citologia , Furões , Humanos , Camundongos , Homem de Neandertal/embriologia , Homem de Neandertal/genética , Neocórtex/embriologia , Neurogênese/genética , Neurogênese/fisiologia , Transcetolase/genética , Transcetolase/metabolismo
20.
Science ; 377(6608): 802, 2022 08 19.
Artigo em Inglês | MEDLINE | ID: mdl-35981035

RESUMO

Embryonic tissue samples reveal how pelvis shape-primed for bipedalism-comes to life.


Assuntos
Evolução Biológica , Genes , Pelve , Humanos , Locomoção , Pelve/anatomia & histologia , Pelve/embriologia
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