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年终盘点：2019年神经发育及成年神经再生十大研究突破
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2019年神经发育及成年神经再生十大研究突破
1. Nature—脊椎动物“新大脑“的进化依赖于神经嵴调节性神经环路的逐渐获得
英文摘要：
The neural crest, an embryonic stem-cell population, is avertebrate innovation that has been proposed to be a key component of the 'newhead', which imbued vertebrates with predatory behaviour1,2. Here,to investigate how the evolution of neural crestcells affected the vertebrate body plan, we examined the molecular circuitsthat control neural crest developmentalong the anteroposterior axis of a jawless vertebrate, the sea lamprey. Geneexpression analysis showed that the cranial subpopulation of the neural crest of the lamprey lacks most components of atranscriptional circuit that is specific to the cranial neuralcrest in amniotes and confers the ability to form craniofacial cartilage ontonon-cranial neural crest subpopulations3.Consistent with this, hierarchical clustering analysis revealed that thetranscriptional profile of the lamprey cranial neuralcrest is more similar to the trunk neural crest ofamniotes. Notably, analysis of the cranial neuralcrest in little skate and zebrafish embryos demonstrated that thetranscriptional circuit that is specific to the cranial neuralcrest emerged via the gradual addition of network components to the neural crest of gnathostomes, which subsequently becamerestricted to the cephalic region. Our results indicate that the ancestral neural crest at the base of the vertebrate lineagepossessed a trunk-like identity. We propose that the emergence of the cranial neural crest, by progressive assembly of anaxial-specific regulatory circuit, allowed the elaboration of the new headduring vertebrate evolution.
参考文献：
Martiket al (2019). Evolution of the new head by gradual acquisition of neural crestregulatory circuits. Nature. 2019 Oct;574(7780):675-678.
2. Science—研究揭示了人类小脑发育中原祖细胞区的时空扩张特征
英文摘要：
Wepresent histological and molecular analyses of the developing human cerebellumfrom 30 days after conception to 9 months after birth. Differences indevelopmental patterns between humans and mice include spatiotemporal expansionof both ventricular and rhombic lip primary progenitor zones to includesubventricular zones containing basal progenitors. The human rhombic lippersists longer through cerebellar developmentthan in the mouse and undergoes morphological changes to form a progenitor poolin the posterior lobule, which is not seen in other organisms, not even in thenonhuman primate the macaque. Disruptions in human rhombic lip development are associated with posterior cerebellarvermis hypoplasia and Dandy-Walker malformation. The presence ofthese species-specific neural progenitorpopulations refines our insight into human cerebellar developmental disorders.
参考文献：
Haldipuret al (2019). Spatiotemporal expansion of primary progenitor zones in thedeveloping human cerebellum. Science. 2019 Oct 25;366(6464):454-460.
3. Cell— 科学家开创了一种方法以研究胚胎发育过程中神经环路是如何涌现的
英文摘要：
Animalsurvival requires a functioning nervous system to develop during embryogenesis.Newborn neurons must assemble into circuits producing activity patterns capableof instructing behaviors. Elucidating how this process is coordinated requiresnew methods that follow maturation and activity of all cells across adeveloping circuit. We present an imaging method for comprehensivelytracking neuron lineages, movements, molecular identities, and activity in theentire developing zebrafish spinal cord, from neurogenesisuntil the emergence of patterned activity instructing the earliest spontaneousmotor behavior. We found that motoneurons are active first and form localpatterned ensembles with neighboring neurons. These ensembles merge,synchronize globally after reaching a threshold size, and finally recruitcommissural interneurons to orchestrate the left-right alternating patternsimportant for locomotion in vertebrates. Individual neurons undergo functionalmaturation stereotypically based on their birth time and anatomical origin. Ourstudy provides a general strategy for reconstructing how functioning circuitsemerge during embryogenesis.
参考文献：
Wan et al (2019). Single-Cell Reconstruction of EmergingPopulation Activity in an Entire Developing Circuit. Cell. 2019 Oct3;179(2):355-372.e23.
4. Cell—在神经系统发育过程中，迁移的神经嵴细胞具有吞噬死亡细胞的功能
英文摘要：
Duringneural tube closure and spinal cord development, many cells die in both the central andperipheral nervous systems (CNS and PNS, respectively). However,myeloid-derived professional phagocytes have not yet colonized the trunk regionduring early neurogenesis. How apoptotic cells areremoved from this region during these stages remains largely unknown. Usinglive imaging in zebrafish, we demonstrate that neuralcrest cells (NCCs) respond rapidly to dying cells and phagocytose cellulardebris around the neural tube. Additionally, NCCshave the ability to enter the CNS through motor exit point transitionzones and clear debris in the spinal cord. Surprisingly, NCCs phagocytosismechanistically resembles macrophage phagocytosis and their recruitment towardcellular debris is mediated by interleukin-1β. Taken together, our resultsreveal a role for NCCs in phagocytosis of debris in the developing nervoussystem before the presence of professional phagocytes.
参考文献：
Zhu et al (2019). Migratory Neural Crest CellsPhagocytose Dead Cells in the Developing Nervous System. Cell. 2019 Sep19;179(1):74-89.e10.
5. Nature—衰老大脑中侵润的T细胞通过干扰素-γ抑制成年神经新生
英文摘要：
Themammalian brain contains neurogenic niches that comprise neuralstem cells and other cell types. Neurogenic niches become less functional withage, but how they change during ageing remains unclear. Here we performsingle-cell RNA sequencing of young and old neurogenic niches in mice. Theanalysis of 14,685 single-cell transcriptomes reveals a decrease in activated neural stem cells, changes in endothelial cells andmicroglia, and an infiltration of T cells in old neurogenic niches. T cellsin old brains are clonally expanded and are generally distinct from those inold blood, which suggests that they may experience specific antigens. Tcells in old brains also express interferon-γ, and the subset of neural stem cells that has a high interferon responseshows decreased proliferation in vivo. We find that T cells can inhibit the proliferationof neural stem cells in co-cultures and in vivo,in part by secreting interferon-γ. Our study reveals an interaction betweenT cells and neural stem cells in old brains,opening potential avenues through which to counteract age-related decline inbrain function.
参考文献：
Dulken et al (2019). Single-cell analysis reveals T cellinfiltration in old neurogenic niches. Nature. 2019 Jul;571(7764):205-210.
6. Science—研究揭示鼠神经嵴细胞细胞命运决定的时空结构特征
英文摘要：
Neural crest cells are embryonic progenitors thatgenerate numerous cell types in vertebrates. With single-cell analysis, we showthat mouse trunk neural crest cells become biasedtoward neuronal lineages when they delaminate from the neuraltube, whereas cranial neural crest cells acquireectomesenchyme potential dependent on activation of the transcription factor Twist1.The choices that neural crest cells make to becomesensory, glial, autonomic, or mesenchymal cells can be formalized as a seriesof sequential binary decisions. Each branch of the decision tree involvesinitial coactivation of bipotential properties followed by gradual shiftstoward commitment. Competing fate programs are coactivated before cellsacquire fate-specific phenotypic traits. Determination of a specific fate isachieved by increased synchronization of relevant programs and concurrentrepression of competing fate programs.
参考文献：
Soldatov et al (2019). Spatiotemporal structure of cellfate decisions in murine neural crest. Science. 2019 Jun 7;364(6444).
7. Nature—中枢神经系统中的神经干细胞迁移到肿瘤中以促进肿瘤神经新生和肿瘤侵袭和复发
英文摘要：
Autonomicnerve fibres in the tumour microenvironment regulate cancer initiation anddissemination, but how nerves emerge in tumours is currently unknown. Here weshow that neural progenitors from the centralnervous system that express doublecortin (DCX+) infiltrate prostatetumours and metastases, in which they initiate neurogenesis.In mouse models of prostate cancer, oscillations of DCX+ neural progenitors in the subventricular zone-aneurogenic area of the central nervous system-are associated with disruption ofthe blood-brain barrier, and with the egress of DCX+ cells into thecirculation. These cells then infiltrate and reside in the tumour, andcan generate new adrenergic neurons. Selective genetic depletion of DCX+cells inhibits the early phases of tumour developmentin our mouse models of prostate cancer, whereas transplantation of DCX+neural progenitors promotes tumour growth andmetastasis. In humans, the density of DCX+ neuralprogenitors is strongly associated with the aggressiveness and recurrence ofprostate adenocarcinoma. These results reveal a unique crosstalk between thecentral nervous system and prostate tumours, and indicate neural targets for the treatment of cancer.
参考文献：
Mauffrey et al(2019). Progenitors from the centralnervous system drive neurogenesis in cancer. Nature. 2019May;569(7758):672-678.
8. Cell—研究发现神经发育和成年神经新生可能均起源于相同的胚胎干细胞
英文摘要：
Newneurons arise from quiescent adult neuralprogenitors throughout life in specific regions of the mammalian brain. Littleis known about the embryonic origin and establishment of adult neural progenitors. Here, we show that Hopx+precursors in the mouse dentate neuroepithelium at embryonic day 11.5 give riseto proliferative Hopx+ neuralprogenitors in the primitive dentate region, and they, in turn, generategranule neurons, but not other neurons, throughout developmentand then transition into Hopx+ quiescent radial glial-like neural progenitors during an early postnatal period.RNA-seq and ATAC-seq analyses of Hopx+ embryonic, early postnatal,and adult dentate neural progenitors furtherreveal common molecular and epigenetic signatures and developmental dynamics.Together, our findings support a "continuous" model wherein a common neural progenitor population exclusively contributes todentate neurogenesis throughout development and adulthood. Adult dentate neurogenesis may therefore represent a lifelongextension of development that maintains heightenedplasticity in the mammalian hippocampus.
参考文献：
Berget al (2019). A Common Embryonic Origin of Stem Cells Drives Developmental andAdult Neurogenesis. Cell. 2019 Apr 18;177(3):654-668.e15.
9. Cell—静息态使衰老大脑中的神经干细胞保持其生存及再生能力
英文摘要：
Thefunction of somatic stem cells declines with age. Understanding the molecularunderpinnings of this decline is key to counteract age-related disease. Here,we report a dramatic drop in the neural stem cells(NSCs) number in the aging murine brain. We find that this smallerstem cell reservoir is protected from full depletion by an increase inquiescence that makes old NSCs more resistant to regenerate the injuredbrain. Once activated, however, young and old NSCs show similar proliferationand differentiation capacity. Single-cell transcriptomics of NSCs indicate thataging changes NSCs minimally. In the aging brain, niche-derived inflammatorysignals and the Wnt antagonist sFRP5 induce quiescence. Indeed, intervention toneutralize them increases activation of old NSCs during homeostasis andfollowing injury. Our study identifies quiescence as a key feature of old NSCsimposed by the niche and uncovers ways to activate NSCs to repair the agingbrain.
参考文献：
Kalamakis et al (2019). Quiescence Modulates Stem CellMaintenance and Regenerative Capacity in the Aging Brain. Cell. 2019 Mar7;176(6):1407-1419.e14.
10. Cell—科学家发现脑类器官是研究人类特异性脑进化的模型
英文摘要：
Directcomparisons of human and non-human primate brains can reveal molecular pathwaysunderlying remarkable specializations of the human brain. However, chimpanzeetissue is inaccessible during neocortical neurogenesiswhen differences in brain size first appear. To identify human-specificfeatures of cortical development, weleveraged recent innovations that permit generating pluripotent stemcell-derived cerebral organoids from chimpanzee. Despite metabolicdifferences, organoid models preserve gene regulatory networks related toprimary cell types and developmental processes. We further identified 261differentially expressed genes in human compared to both chimpanzeeorganoids and macaque cortex, enriched for recent gene duplications, andincluding multiple regulators of PI3K-AKT-mTOR signaling. We observedincreased activation of this pathway in human radial glia, dependent on tworeceptors upregulated specifically in human: INSR and ITGB8. Our findingsestablish a platform for systematic analysis of molecular changes contributingto human brain development and evolution.
参考文献：
Pollen et al (2019). Establishing Cerebral Organoids asModels of Human-Specific Brain Evolution. Cell. 2019 Feb 7;176(4):743-756.e17.
2019年十大研究进展名录
6. 年终盘点：2019年抑郁症领域十大基础研究进展（一半来自中国）
11. 年终盘点：2019年医学和生物学领域深度学习和神经网络十大基础研究进展
2018年十大研究进展名录
14. 2018年的十大睡眠研究突破
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