Franz Weber, …, Yang Dan* Control of REM sleep by ventral medulla GABAergic neurons. Nature 526:435–438 (2015) https://www.nature.com/articles/nature14979 の論文の要旨が非常にかっちりと組み立てられていて無駄も隙もない文章構成だと思ったので、分析してみます。以下、英文 分析 の順です
Rapid eye movement (REM) sleep 主題を最初の文の文頭において明示 is a distinct brain state characterized by activated electroencephalogram and complete skeletal muscle paralysis, and is associated with vivid dreams1,2,3. 主題の説明Transection studies by Jouvet first demonstrated that the brainstem is both necessary and sufficient for REM sleep generation2,既知の事柄の紹介and the neural circuits in the pons have since 副詞（それ以来）介been studied extensively4,5,6,7,8. 研究の潮流の紹介The medulla also contains neurons that are active during REM sleep9,10,11,12,13, 既知の事柄の紹介but whether they play a causal role in REM sleep generation remains unclear. 問題提起Here we show that a GABAergic (γ-aminobutyric-acid-releasing) pathway originating from the ventral medulla powerfully promotes REM sleep in mice. 提起した問題に対する簡潔な答え（実験結果の要約）Optogenetic activation of ventral medulla GABAergic neurons rapidly and reliably initiated REM sleep episodes and prolonged their durations, whereas inactivating these neurons had the opposite effects. もう少し詳細な実験結果Optrode recordings from channelrhodopsin-2-tagged ventral medulla GABAergic neurons showed that they were most active during REM sleep (REMmax), and during wakefulness they were preferentially active during eating and grooming. 同様の結論を導く別の実験結果Furthermore, dual retrograde tracing showed that the rostral projections to the pons and midbrain and caudal projections to the spinal cord originate from separate ventral medulla neuron populations. 別の実験結果（先行研究とつながる重要な発見） Activating the rostral GABAergic projections was sufficient for both the induction and maintenance of REM sleep, 実験結果の簡潔な要約・結論which are probably mediated in part by inhibition of REM-suppressing GABAergic neurons in the ventrolateral periaqueductal grey. 推測を交えた補足 These results identify a key component of the pontomedullary network controlling REM sleep. 意義、結論（抽象化した表現）The capability to induce REM sleep on command may offer a powerful tool for investigating its functions. 将来展望・研究領域への期待される波及効果
Physiological Correlates of Prolonged Sleep Deprivation in Rats ALLAN RECHTSCHAFFEN, MARCIA A. GILLILAND, BERNARD M. BERGMANN, AND JACQUELINE B. WINTERAuthors Info & Affiliations SCIENCE 8 Jul 1983 Vol 221, Issue 4606 pp. 182-184 DOI: 10.1126/science.6857280
Regularly Occurring Periods of Eye Motility, and Concomitant Phenomena, During Sleep EUGENE ASERINSKY AND NATHANIEL KLEITMANAuthors Info & Affiliations SCIENCE 4 Sep 1953 Vol 118, Issue 3062 pp. 273-274 DOI: 10.1126/science.118.3062.273
Growth hormone secretion during sleep Y. Takahashi, … , D. M. Kipnis, W. H. Daughaday Published September 1, 1968 Citation Information: J Clin Invest. 1968;47(9):2079-2090. https://doi.org/10.1172/JCI105893.
Electroencephalogr Clin Neurophysiol . 1997 Sep;103(3):405-8. doi: 10.1016/s0013-4694(97)00013-1. Temporal relationships between pulsatile cortisol secretion and electroencephalographic activity during sleep in man C Gronfier 1, R Luthringer, M Follenius, N Schaltenbrand, J P Macher, A Muzet, G Brandenberger PMID: 9305289.
Sleep drives metabolite clearance from the adult brain Lulu Xie 1, Hongyi Kang, Qiwu Xu, Michael J Chen, Yonghong Liao, Meenakshisundaram Thiyagarajan, John O’Donnell, Daniel J Christensen, Charles Nicholson, Jeffrey J Iliff, Takahiro Takano, Rashid Deane, Maiken Nedergaard Science . 2013 Oct 18;342(6156):373-7. doi: 10.1126/science.1241224.
Sleep promotes branch-specific formation of dendritic spines after learning Guang Yang, Cora Sau Wan Lai, Joseph Cichon, Lei Ma, Wei Li, Wen-Biao Gan Science . 2014 Jun 6;344(6188):1173-8. doi: 10.1126/science.1249098.
Arch Ital Biol . 1962:100:125-206. [Research on the neural structures and responsible mechanisms in different phases of physiological sleep] [Article in French] M JOUVET PMID: 14452612
Arch Ital Biol . 1989 Jun;127(3):133-64. Mapping of cholinoceptive brainstem structures responsible for the generation of paradoxical sleep in the cat G Vanni-Mercier 1, K Sakai, J S Lin, M Jouvet https://pubmed.ncbi.nlm.nih.gov/2774793/ a high amount of paradoxical sleep (PS) was induced by carbachol applications with short latencies, less than 5 minutes, is the mediodorsal pontine tegumentum, namely the nuclei locus coeruleus (LC) alpha and peri-LC alpha, where ChAT-and TH- immunoreactive neurons are intermingled.
Mapping neuronal inputs to REM sleep induction sites with carbachol-fluorescent microspheres J J Quattrochi 1, A N Mamelak, R D Madison, J D Macklis, J A Hobson Science 1989 Sep 1;245(4921):984-6. doi: 10.1126/science.2475910. The cholinergic agonist carbachol was conjugated to latex microspheres that were fluorescently labeled with rhodamine and used as neuroanatomical probes that show little diffusion from their injection site and retrogradely label neurons projecting to the injection site. Microinjection of this pharmacologically active probe into the gigantocellular field of the cat pontine brain stem caused the awake cats to fall into rapid eye movement (REM) sleep indistinguishable from that produced by free carbachol.
A putative flip-flop switch for control of REM sleep Jun Lu 1, David Sherman, Marshall Devor, Clifford B Saper Nature . 2006 Jun 1;441(7093):589-94. doi: 10.1038/nature04767. Epub 2006 May 10. PMID: 16688184 DOI: 10.1038/nature04767 Figure 3: The interrelationship of the two halves of the REM switch.
REM睡眠に関与する脳部位はほかにもいくつも発見されており、どれが重要なのかが混沌とした印象です。
Chung, S., Weber, F., Zhong, P. et al. Identification of preoptic sleep neurons using retrograde labelling and gene profiling.Nature545, 477–481 (2017). https://doi.org/10.1038/nature22350 Electrophysiological recordings and c-Fos immunohistochemistry have shown the existence of sleep-active neurons in the preoptic area, especially in the ventrolateral preoptic area and median preoptic nucleus.
Weber, F., Chung, S., Beier, K. et al.Control of REM sleep by ventral medulla GABAergic neurons.Nature526, 435–438 (2015). https://doi.org/10.1038/nature14979 Transection studies by Jouvet first demonstrated that the brainstem is both necessary and sufficient for REM sleep generation, and the neural circuits in the pons have since been studied extensively. The medulla also contains neurons that are active during REM sleep, but whether they play a causal role in REM sleep generation remains unclear. Here we show that a GABAergic (γ-aminobutyric-acid-releasing) pathway originating from the ventral medulla powerfully promotes REM sleep in mice.
The cellular and molecular mechanisms of vertebrate lensdevelopment November 2014 Development 141(23):4432-4447 DOI: 10.1242/dev.107953 CC BY 3.0 https://www.researchgate.net/publication/268985222_The_cellular_and_molecular_mechanisms_of_vertebrate_lens_development#fullTextFileContent
Whole-mount in situ hybridization of E7.5 (A), E8.5 (B), E9.5 (C and D), E10.5 (E and F), and E11.5 mouse embryos (G and H). rax, a novel paired-type homeobox gene, shows expression in the anterior neural fold and developing retina Takahisa Furukawa *, Christine A Kozak †, Constance L Cepko *,‡ Proc Natl Acad Sci U S A. 1997 Apr 1;94(7):3088–3093. doi: 10.1073/pnas.94.7.3088 ”pax6 expression starts later than that of rax, suggesting that rax might be directly or indirectly upstream of pax6 in the series of events that lead to optic vesicle formation.” https://pmc.ncbi.nlm.nih.gov/articles/PMC20326/
RAX遺伝子破壊マウスでは眼の形成ができません。
An essential role for Rax in retina and neuroendocrine system development Yuki Muranishi, Koji Terada, Takahisa Furukawa First published: 24 April 2012 https://doi.org/10.1111/j.1440-169X.2012.01337.x DGD https://onlinelibrary.wiley.com/doi/10.1111/j.1440-169X.2012.01337.x
PAX6
眼の発生のマスター遺伝子の一つであるPAX6を欠損させたマウスでは眼が全くできなくなります。
Anophthalmia mouse mutant. a Head of a neonatal (P1) homozygous Pax6Aey11 mutant compared to a wild-type mouse (wt) at the same age. The absence of eyes in the mutant is obvious. The eyelids of neonatal mice are still closed (photography: Jana Löster†, unpublished). Mouse models for microphthalmia, anophthalmia and cataracts 27 March 2019 Volume 138, pages 1007–1018, (2019)https://link.springer.com/article/10.1007/s00439-019-01995-w
カエルの眼の発生に関わるマスター遺伝子の発現パターン
Specification of the vertebrate eye by a network of eye field transcription factors Michael E. Zuber, Gaia Gestri, Andrea S. Viczian, Giuseppina Barsacchi, William A. Harris Author and article information Development (2003) 130 (21): 5155–5167. https://journals.biologists.com/dev/article/130/21/5155/52150/Specification-of-the-vertebrate-eye-by-a-network
Figure 2. Expression of Bmp4 and BMP type-I receptor genes during early eye development. (A–F) In situ hybridization using an antisense riboprobe for Bmp4 on transverse sections of 10- (A) and 14- (B) somite-stage embryos, and on frontal sections of 18- (C), 22- (D), 27- (E), and ∼40-somite-stage (10.5 dpc) (F) embryos.
BMP4 is essential for lens induction in the mouse embryo Yasuhide Furuta and Brigid L.M. Hogan1 Genes & Dev. 1998. 12: 3764-3775 https://genesdev.cshlp.org/content/12/23/3764.full
Figure 3. The timing and intensity of FGF signalling controls the two-dimensional patterning of the lens. The PPR is first selected from the head ectoderm by active FGF signalling devoid of suppressive BMP and Wnt (a), before progressing further towards the LP fate in lieu of（～の代わりに◆instead of に近い意味） continuous FGF signalling (b). FGF next induces Frs2–Shp2-mediated Ras signalling modulated by NF1 to promote Pax6 expression and lens vesicle invagination (c), but FGF signalling must be suppressed by Spry to allow lens vesicle closure (d). During the subsequent lens maturation, FGF cooperates with PDGF to stimulate Notch signalling, which promotes lens epithelium proliferation (e). In lens fibre cells, FGF signalling also activates Ras to promote differentiation and recruit Ras and Rac GTPases via Crk/CrkL to promote cell elongation (f).
レンズの前後軸の決定に関わる分泌シグナル：WNTとFGF
Fig. 2. Diagram indicating how the ocular media and a gradient of FGF stimulation may determine antero-posterior patterns of lens cell behavior. Growth factor regulation of lens development F.J. Lovicu , J.W. McAvoy Developmental Biology Volume 280, Issue 1, 1 April 2005, Pages 1-14 https://www.sciencedirect.com/science/article/pii/S001216060500045X?via%3Dihub
Lhx2 links the intrinsic and extrinsic factors that control optic cup formation Sanghee Yun, Yukio Saijoh, Karla E. Hirokawa, Daniel Kopinke, L. Charles Murtaugh, Edwin S. Monuki, Edward M. Levine Author and article information Development (2009) 136 (23): 3895–3906. https://journals.biologists.com/dev/article/136/23/3895/43745/Lhx2-links-the-intrinsic-and-extrinsic-factors
FIGURE 4 | Early ocular morphogenesis. The Use of Induced Pluripotent Stem Cells as a Model for Developmental Eye Disorders July 2020 Frontiers in Cellular Neuroscience 14:265 DOI: 10.3389/fncel.2020.00265 License CC BY (A) Developmental pathways such as Wnt, BMP, and fibroblast growth factor (FGF) drive upregulation of eye-field transcription factors in the anterior neural plate, creating the specified region known as the “eye-field.”
3D Embryology of Pharyngeal arches, Pharyngeal Pouches, Pharyngeal clefts and Pharyngeal Apparatus MedicoVisual – Visual Medical Lectures チャンネル登録者数 4.69万人
Epithelial-Mesenchymal Transitions in Development and Disease Cell Volume 139, Issue 5p871-890November 25, 2009 https://www.cell.com/fulltext/S0092-8674%2809%2901419-6
Epithelial–mesenchymal transition and its transcription factors Biosci Rep. 2021 Dec 23;42(1):BSR20211754. doi: 10.1042/BSR20211754 https://pmc.ncbi.nlm.nih.gov/articles/PMC8703024/
Differential Role of Snail1 and Snail2 Zinc Fingers in E-cadherin Repression and Epithelial to Mesenchymal Transition* J Biol Chem. 2013 Dec 1;289(2):930–941. doi: 10.1074/jbc.M113.528026 https://pmc.ncbi.nlm.nih.gov/articles/PMC3887216/
During embryogenesis, epithelia are considered to be highly plastic and able to switch back and forth between epithelia and mesenchyme, via the processes of epithelial-mesenchymal transition (EMT) and mesenchymal-epithelial transition (MET), respectively. https://www.jci.org/articles/view/39675
Epithelial to mesenchymal transition during gastrulation: An embryological view Yukiko Nakaya, Guojun Sheng First published: 25 November 2008 https://doi.org/10.1111/j.1440-169X.2008.01070.x Development, Growth and Differentiation (DGD)
発生における上皮間葉転換
Embryonic development depends on epithelial cells changing into migratory mesenchymal cells, and then changing back into epithelial cells when they reach their destination. These interlinked cellular dynamics, termed epithelial-mesenchymal transition (EMT) and mesenchymal-epithelial transition (MET), have long been recognized as fundamental processes that drive development [1]. https://biosignaling.biomedcentral.com/articles/10.1186/s12964-021-00761-8
The transition of epithelial to mesenchymal cells is not irreversible, as several rounds of EMT and MET are necessary for the final differentiation of specialized cell types and the acquisition of the complex three-dimensional structure of internal organs. Accordingly, these sequential rounds are referred to as primary, secondary, and tertiary EMT (Figure 1). （Cell Volume 139, Issue 5, 25 November 2009, Pages 871-890 Review Epithelial-Mesenchymal Transitions in Development and Disease）
Cellular plasticity is fundamental to embryonic development. The importance of cellular transitions in development is first apparent during gastrulation when the process of epithelial to mesenchymal transition transforms polarized epithelial cells into migratory mesenchymal cells that constitute the embryonic and extraembryonicmesoderm. https://cir.nii.ac.jp/crid/1364233269608738688
Thomas J. Carroll, Joo-Seop Park, Shigemi Hayashi, Arindam Majumdar, Andrew P. McMahon, Wnt9b Plays a Central Role in the Regulation of Mesenchymal to Epithelial Transitions Underlying Organogenesis of the Mammalian Urogenital System, Developmental Cell,Volume 9, Issue 2,2005,Pages 283-292,ISSN 1534-5807, https://doi.org/10.1016/j.devcel.2005.05.016.
レビュー論文
EMT programmes to normal and neoplastic epithelial stem cells.Nat Rev Cancer21, 325–338 (2021). Lambert, A.W., Weinberg, R.A. Linking https://doi.org/10.1038/s41568-021-00332-6
Prepubertal vulvovaginitis January 2018Journal of Nature and Science of Medicine 2(1) DOI:10.4103/JNSM.JNSM_33_18 License CC BY-NC-SA The majority of cases are due to nonspecific vulvovaginitis in which vaginal cultures will grow organisms considered to be part of the normal flora. The condition is easily managed with good perineal hygiene. In reluctant cases, oral antibiotics or local estrogen cream may be helpful.
