Transcriptional Regulation and Implications for Controlling Hox Gene Expression Zainab Afzal and Robb Krumlauf J Dev Biol. 2022 Mar; 10(1): 4. 2022 Jan 10. doi: 10.3390/jdb10010004 PMCID: PMC8788451
Genesis. 2019 Jul-Aug; 57(7-8): e23296. Published online 2019 Apr 25. doi: 10.1002/dvg.23296 PMCID: PMC6767176 PMID: 31021058 What are the roles of retinoids, other morphogens, and Hox genes in setting up the vertebrate body axis? Antony J. Durstoncorresponding author 1
Hox Genes in the Adult Skeleton: Novel Functions Beyond Embryonic Development Dev Dyn. 2017 Apr; 246(4): 310–317. Published online 2017 Jan 27. doi: 10.1002/dvdy.24482 PMCID: PMC5508556 NIHMSID: NIHMS875514 PMID: 28026082
成体におけるHOX遺伝子
Hox Genes in the Adult Skeleton: Novel Functions Beyond Embryonic Development Dev Dyn. 2017 Apr; 246(4): 310–317. Published online 2017 Jan 27. doi: 10.1002/dvdy.24482 PMCID: PMC5508556 NIHMSID: NIHMS875514 PMID: 28026082 Continued regional expression of Hox genes in adult tissues has been suggested by several independent studies, largely by the characterization of cells in culture.
HOX GENES: Seductive Science, Mysterious Mechanisms Ulster Med J. 2006 Jan; 75(1): 23–31. PMCID: PMC1891803 PMID: 16457401 They are expressed during embryonic development in a highly co-ordinated manner and continue to be expressed in virtually all tissues and organs throughout adult life.
成体におけるHO
HOX遺伝子群による体軸上の位置決定に関する論文（原著・総説）
What are the roles of retinoids, other morphogens, and Hox genes in setting up the vertebrate body axis? Genesis. 2019 Jul-Aug; 57(7-8): e23296. Published online 2019 Apr 25. doi: 10.1002/dvg.23296 PMCID: PMC6767176 the core patterning mechanism is timing: BMP‐anti BMP mediated time space translation that regulates Hox temporal and spatial collinearities and Hox‐Hox auto‐ and cross‐ regulation. The known anterior–posterior morphogens and signaling pathways––retinoids, FGF’s, Cdx, Wnts, Gdf11 and others––interact with this core mechanism at and after space–time defined “decision points,” leading to the separation of distinct axial domains.
Limb positioning and initiation: an evolutionary context of pattern and formation Dev Dyn. Author manuscript; available in PMC 2023 Nov 3. Published in final edited form as: Dev Dyn. 2021 Sep; 250(9): 1264–1279. Published online 2021 Feb 15. doi: 10.1002/dvdy.308 PMCID: PMC10623539
Timed Collinear Activation of Hox Genes during Gastrulation Controls the Avian Forelimb Position Chloe Moreau Paolo Caldarelli Didier Rocancourt Nicolas Denans Olivier Pourquie Jerome Gros December 13, 2018 DOI:https://doi.org/10.1016/j.cub.2018.11.009 Current Biology VOLUME 29, ISSUE 1, P35-50.E4, JANUARY 07, 2019
Review Article Molecular and evolutionary basis of limb field specification and limb initiation Mikiko Tanaka Develop. Growth Differ. (2013) 55, 149–163 (PDF) In tetrapods, motoneurons that innervate the limbs form lateral motor columns (LMCs) at the brachial and lumbar levels of the spinal cord, and the LMC identities in opposite forelimbs and hindlimbs are defined by expression of Hox6 and Hox10, respectively, in the spinal cord (Dasen et al. 2003; Shah et al. 2004; Wu et al. 2008).
Hox9 genes and vertebrate limb specification. Cohn, M., Patel, K., Krumlauf, R. et al.Nature387, 97–101 (1997). https://doi.org/10.1038/387097a0 無料要旨 Hox genes are good candidates for encoding position in lateral plate mesoderm along the body axis and thus for determining where limbs are formed. Local application of fibroblast growth factors (FGFs) to the anterior prospective flank of a chick embryo induces development of an ectopic wing, and FGF applied to posterior flank induces an ectopic leg.
The mesenchymal factor, FGF10, initiates and maintains the outgrowth of the chick limb bud through interaction with FGF8, an apical ectodermal factor Hideyo Ohuchi, Takashi Nakagawa, Atsuyo Yamamoto, Akihiro Araga, Takeshi O 01 JUNE 1997 DEVＥＬＯＰＭＥＮＴ チックのデータとモデル図
The roles of FGFs in the early development of vertebrate limbs Genes & Dev. 1998. 12: 1571-1586
Fibroblast Growth Factor 10 and Vertebrate Limb Development Libo Jin,1 Jin Wu,1 Saverio Bellusci,1,2,3,* and Jin-San Zhang1,2,4,* Front Genet. 2018; 9: 705. Published online 2019 Jan 7. doi: 10.3389/fgene.2018.00705 PMCID: PMC6338048 PMID: 30687387
J:71694 Bruneau S, et al., Dev Biol. 2001 Sep 15;237(2):345-53 https://www.informatics.jax.org/image/MGI:2153107
FGF8とFGF4の関係
こういう論文があります。
Biochemical and Biophysical Research Communications Volume 209, Issue 3, 26 April 1995, Pages 809-816 Biochemical and Biophysical Research Communications Regular Article An Additional Limb Can Be Induced from the Flank of the Chick Embryo by FGF4
BMP signals control limb interdigital programmed cell death by regulating FGF signaling Save Related Papers Chat with paper July 2007Development 134(12):2359-68 DOI:10.1242/dev.001677 https://www.researchgate.net/figure/Fgf4-and-Fgf8-expression-is-upregulated-in-mutant-forelimbs-A-L-Fgf8-and-M-X-Fgf4_fig5_6298017
四肢の前後軸の決定に関与するシグナル分子
Coordinate expression of the murine Hox-5 complex homoeobox-containing genes during limb pattern formation. Dollé, P., Izpisúa-Belmonte, JC., Falkenstein, H. et al.Nature342, 767–772 (1989). https://doi.org/10.1038/342767a0 本文有料
A Dual Role for Hox Genes inLimb Anterior-PosteriorAsymmetry SCIENCE VOL 304 11 JUNE 2004 Full text at ResearchGate
Mutual transcriptional repression between Gli3 and Hox13 genes determines the anterior-posterior asymmetry of the autopod Ma Félix Bastida, Rocío Pérez-Gómez, Anna Trofka, Rushikesh Sheth, H. Scott Stadler, Susan Mackem, Marian A. Ros doi: https://doi.org/10.1101/419606 https://www.biorxiv.org/content/10.1101/419606v1.full
指の形成
HOXA13 regulates the expression of bone morphogenetic proteins 2 and 7 to control distal limb morphogenesis ２００４ Full text at ResearchGate
四肢の形成 講義動画
Introduction to Limb Development Kate Lee チャンネル登録者数 358人
Introduction to Limb Development Kate Lee チャンネル登録者数 358人 (21:27) 講師：Dr. Michael J. F. Barresi, Biological Sciences Smith College（ゼブラフィッシュ神経発生の研究者） stylopod – zeugopod – autopod という呼称は、馬でも人でも一見、形が違うようにみえても共通で使われる。HOX遺伝子や分子シグナルに言及した講義 Tbx5, Tbx4, FGF10, shh、Lmx1、BMP, 体軸に沿ったHOX遺伝子によるコード、四肢のproximalからdistalにむかう軸にそったHOX遺伝子コード、手のanterior-posterior軸に関するHOX遺伝子コード、手の背側-腹側の軸を決めるシグナル、AER, ZPA、移植実験など。
The squamous part of the temporal bone (or squamous temporalis/squamous temporal bone) is a very thin bone and forms the anterosuperior aspect of the temporal bone. https://radiopaedia.org/articles/squamous-part-of-temporal-bone
神経堤細胞から発生する構造
Martik, M.L., Bronner, M.E. Riding the crest to get a head: neural crest evolution in vertebrates.Nat Rev Neurosci22, 616–626 (2021). https://doi.org/10.1038/s41583-021-00503-2 無料要旨 In their seminal 1983 paper, Gans and Northcutt proposed that evolution of the vertebrate ‘new head’ was made possible by the advent of the neural crest and cranial placodes. The neural crest is a stem cell population that arises adjacent to the forming CNS and contributes to important cell types, including components of the peripheral nervous system and craniofacial skeleton and elements of the cardiovascular system. In the past few years, the new head hypothesis has been challenged by the discovery in invertebrate chordates of cells with some, but not all, characteristics of vertebrate neural crest cells.
Diabetes, Oxidative Stress, and DNA Damage Modulate Cranial Neural Crest Cell Development and the Phenotype Variability of Craniofacial Disorders REVIEW article Front. Cell Dev. Biol., 20 May 2021 Sec. Molecular and Cellular Pathology Volume 9 – 2021 | https://doi.org/10.3389/fcell.2021.644410
The Special Developmental Biology of Craniofacial Tissues Enables the Understanding of Oral and Maxillofacial Physiology and Diseases Int. J. Mol. Sci. 2021, 22(3), 1315; https://doi.org/10.3390/ijms22031315
First arch (mandibular) Skeletal structures, ligaments: Malleus 槌骨（つちこつ、ついこつ 中耳にあるハンマー（槌）の形をした小さい骨）, short limb of incus キヌタ骨, maxilla 上顎骨, zygomatic bone 頬骨, hard palate, vomer bone 鋤骨, mandibule 下顎骨, temporal bone (squamous); anterior ligament of malleus, sphenomandibular ligament
Second arch (hyoid) Skeletal structures, ligaments: Stapes 鐙骨（あぶみこつ 中耳にある骨で内耳へ音の振動を伝達する。） long limb of incus incus キヌタ骨(砧骨 音の振動を伝える中耳の三つの耳小骨の一つ), styloid process, lesser horn and upper part of body of hyoid bone 舌骨; stylohyoid ligament
Figure 3 E-cadherin localization changes during preimplantation development. E-cadherin is distributed throughout the membrane until the late 8-cell stage. Then, it begins to accumulate in cell–cell junctions and is predominantly localized to basolateral regions by the 16-cell stage.
Figure 5 Adhesion and polarity determine cell fate in the preimplantation mouse embryo. The apical polarity complex in outer cells sequesters components of the Hippo signaling pathway preventing its activation. Unphosphorylated Yap can enter the nucleus and drive expression of trophectoderm-specific genes. In inner cells, Amot localizes to adherens junctions where it binds to Lats1/2 and the E-cadherin adhesion complex via Nrf2. Lats 1/2 phosphorylates Amot, activating it and this complex phosphorylates Yap. Phosphorylated Yap is excluded from the nucleus and the Hippo pathway is activated, allowing transcription of inner cell mass specific genes.
Implantation and Trophoblast by Peter Ward, PhD https://app.lecturio.com/#/lecture/s/6528/10360/44662
胚盤胞で発現する遺伝子と全能性、多能性
Embryonic Stem Cells（ES細胞）とは？（https://www.ncbi.nlm.nih.gov/books/NBK223690/）Embryonic stem cells (ESCs) are found in the inner cell mass of the human blastocyst, an early stage of the developing embryo lasting from the 4th to 7th day after fertilization. In normal embryonic development, they disappear after the 7th day, and begin to form the three embryonic tissue layers. ESCs extracted from the inner cell mass during the blastocyst stage, however, can be cultured in the laboratory and under the right conditions will proliferate indefinitely. ESCs growing in this undifferentiated state retain the potential to differentiate into cells of all three embryonic tissue layers.
Changes in OCT4 expression play a crucial role in the lineage specification and proliferation of preimplantation porcine blastocysts Cell Prolif. 2022 Nov; 55(11): e13313. Published online 2022 Jul 26. doi: 10.1111/cpr.13313 PMCID: PMC9628253
Differential Role for Transcription Factor Oct4 Nucleocytoplasmic Dynamics in Somatic Cell Reprogramming and Self-renewal of Embryonic Stem Cells* J Biol Chem. 2013 May 24; 288(21): 15085–15097. Published online 2013 Apr 11. doi: 10.1074/jbc.M112.448837 PMCID: PMC3663529 PMID: 23580657 Results: Oct4 is a nucleocytoplasmic shuttling protein, and Oct4 mutants with biased nucleocytoplasmic localization show limited potential for cellular reprogramming.
Molecules in pathogenesis Subcellular localisation of the stem cell markers OCT4, SOX2, NANOG, KLF4 and c-MYC in cancer: a reviewhttps://jcp.bmj.com/content/71/1/88
Spatiotemporal dynamics of OCT4 protein localization during preimplantation development in mice 2016年 https://doi.org/10.1530/REP-16-0277 A recent study reported that OCT4A, which is crucial for establishment and maintenance of pluripotent cells, is expressed in oocytes, but maternal OCT4A is dispensable for totipotency induction. Whereas another study reported that OCT4B, which is not related to pluripotency, is predominantly expressed instead of OCT4A during early preimplantation phases in mice. ややこしい話
Introduction to Histology (37:42) The Noted Anatomist チャンネル登録者数 54.7万人 組織学で染色像をどう読み取るかが学べそうです。独学で組織学の教科書を読むのは無理ゲーに思えますが、この動画の説明は実にわかりやすい。組織染色像を見るときのポイントがわかります。
A further aspect of this classification system requiring clarification is the place of EndMT. The endothelium is a specialized form of squamous epithelial tissue, and as such, EndMT is a sub-category of EMT.
The largest blood vessels are arteries and veins, which have a thick, tough wall of connective tissue and and many layers of smooth muscle cells (Figure 22-22). The wall is lined by an exceedingly thin single sheet of endothelial cells, the endothelium, separated from the surrounding outer layers by a basal lamina. The amounts of connective tissue and smooth muscle in the vessel wall vary according to the vessel’s diameter and function, but the endothelial lining is always present.
The human hair fiber can be described as a long, thin, cylindrical, and flexible shaft consisting of a core covered by relatively thin and flat, but circumferentially curved, overlapping cuticle cells. The core, or cortex, is composed of elongated, keratinized cells aligned, or slightly inclined with the direction of the longitudinal fiber axis, and often contains a centrally located, strand of highly vacuolated hardened cell remnants known as medulla cells (Orwin, 1979a).
Cortical cell types and intermediate filament arrangements correlate with fiber curvature in Japanese human hair Journal of Structural Biology Volume 166, Issue 1, April 2009, Pages 46-58 Journal of Structural Biology https://www.sciencedirect.com/science/article/abs/pii/S1047847708002980
細胞からできているといっても、ケラチンを多量に産生して一生を終えた細胞ということだと思います。
Hair is a keratinous filament growing out of the epidermis. It is primarily made of dead, keratinized cells.
An early theory to explain human development, dating back more than two thousands years, is that of preformation. This theory provided a simple answer: we already contain in our bodies very small but fully formed members of the next generation, who merely grow within the mother until they reach the size of a baby able to survive outside the womb. Many scientists thought they saw this tiny person—which they called a homunculus—when they peered at sperm through the first microscopes in the seventeenth century.
UCLAのRoger Gorskiの研究（1990）によれば分界条床核（ぶんかいじょうしょうかく） Bed nucleus of stria terminalis (BNST)の大きさが女性よりも男性のほうがずっと大きい（2倍以上）のだそう。
別の研究で、オランダのDick F. Swaabの研究によれば前視床下部間質核（ぜんししょうかぶかんしつかく）Interstitial nucleus of the anterior hypothalamus (INAH)の大きさが男性の方が大きいのだそう。
解剖学的な差は見つかっているとして、それと性自認とどうつながるのか（つながらないのか）のでしょうか。Kruijvert et al., 2000の論文によると、体が男性で性自認が女性の人（Male to Female Transsexual; M to F)の場合には、分界条床核のソマトスタチン陽性神経細胞の数が「女性と同様」で男性の半分くらいしかなかったそうです。ちなみに男性のゲイの人の場合には、男性と差がなかったのだそう。このことから分界条床核はジェンダー・アイデンティティと関係があると考えられているそう。
では大脳皮質においても性差があるのでしょうか。『話を聞かない男 地図が読めない女』（2002年）という本が昔ベストセラーになりましたが、どうやら違いがあるようです。ブロックを空間で回転させるように頭でイメージするテストは男性のほうが成績が良かったという論文があるそう。また、別の研究ではBrain activation during human navigation: gender-differnet neural networks ans substrate of performanceという論文があるそう。
Grön, G., Wunderlich, A., Spitzer, M. et al.Brain activation during human navigation: gender-different neural networks as substrate of performance.Nat Neurosci3, 404–408 (2000). https://doi.org/10.1038/73980
Are male and female brains different? – BBC REEL BBC Reel チャンネル登録者数 48.5万人 ”Have wee actually found any differences between the brains of MEN and the brains of WOMEN?” ”The answer is: NO.” (1分12秒～）
アンドロゲン・シャワー仮説
下の創設では、アンドロゲンシャワーは性自認には影響しないと述べています。
Increasing evidence confirms that prenatal androgens have facilitative effects on male-typed activity interests and engagement (including child toy preferences and adult careers), and spatial abilities, but relatively minimal effects on gender identity.
Curr Opin Behav Sci. 2016 Feb; 7: 53–60. doi: 10.1016/j.cobeha.2015.11.011 PMCID: PMC4681519 NIHMSID: NIHMS740435 PMID: 26688827 How Early Hormones Shape Gender Development Sheri A. Berenbauma and Adriene M. Beltzb
Early androgen exposure and human gender development Melissa Hines,Mihaela Constantinescu, and Debra Spencer Biol Sex Differ. 2015; 6: 3. Published online 2015 Feb 26. doi: 10.1186/s13293-015-0022-1 PMCID: PMC4350266 PMID: 25745554
In mammals, the existence of primitive endoderm and its association with both the extra-embryonic yolk sac and the embryo proper had been noted at the end of the 19th century. The primitive endoderm underlying the primitive ectoderm/epiblast became known as visceral endoderm, whereas that on the maternal side became parietal endoderm, as first recognized by Duval and Sobotta (Duval, 1891; Sobotta, 1911)
However, many years passed before it became clear that the primitive endoderm is replaced by definitive endoderm, which mainly gives rise to the lining of the gut. The first clear experimental demonstration came from the careful experiments of Bellairs, who combined electron and light microscopy, cell marking and experimental embryology. Bellairs established that the deep layer of ‘endoderm’ present in chick embryos before the appearance of the primitive streak contributes to the extra-embryonic yolk sac stalk (Bellairs, 1953a; Bellairs, 1953b). Thus, the early chick embryo contains a transitory, extra-embryonic cell layer at its ventral surface. Its name, ‘endoderm’, was replaced by the term ‘hypoblast’, to distinguish it from definitive gut endoderm, which, as shown by Bellairs, is derived from the epiblast via ingression through the primitive streak, replacing the hypoblast.
Hypoblast cells form an extraembryonic cell layer on the surface of the inner cell mass and faces the blastocoelic cavity. It gives rise to the visceral and parietal endoderm. The hypoblast cells are separated from the epiblast layer by an extracellular basement membrane. Notes These cells are evident from E7 in mouse development. Lineage marker transcription factors are: SOX17, GATA4, GATA6, PDGFRa. Human hypoblast differentiation differs from that observed in mouse, rat and cow embryos in their absence of appreciable Laminin expression in the presumptive hypoblast and downregulation of GATA6 in a subset of SOX17-expressing cells. This, in addition to different reactions to FGF/Erk signaling inhibitors, suggests that the human hypoblast may segregate by unique mechanisms.
No evidence of involvement of E-cadherin in cell fate specification or the segregation of Epi and PrE in mouse blastocysts Katarzyna Filimonow,Nestor Saiz,Aneta Suwińska,Tomasz Wyszomirski,Joanna B. Grabarek,Elisabetta Ferretti,Anna Piliszek,Berenika Plusa ,Marek Maleszewski Published: February 8, 2019 PLoS One. 2019; 14(2): e0212109. https://doi.org/10.1371/journal.pone.0212109
Blastocyst development embryology.med.unsw.edu.au (Greek, blastos = sprout + cystos = cavity) or blastula, the term used to describe the hollow cellular mass that forms in early development.
胞を作っている部分が、trophoblast 栄養外胚葉で、その内側に細胞の塊が存在しており、inner cell mass 内細胞塊と呼ばれます。inner cell mass 内細胞塊は、embryoblast 胚芽（はいが）とも呼ばれます。将来、ヒトの体になるのがこのinner cell mass 内細胞塊です。
The hypoblast forms a squamous epithelium covering the epiblast58 and expands beyond the epiblast margin. At this stage, hypoblast cells diversify into visceral and parietal endoderm (Fig. 2). Visceral endoderm overlies the epiblast and gives rise to a cuboidal epithelium. The peripheral hypoblast cells become parietal endoderm, which forms an inner lining of the trophoblast. Both visceral and parietal endoderm contribute to the primary yolk sac55,59.
Carlson FIG.5.2 および本文 “The epiblast contains the cells that make up the embryo itself, but extraembryonic tissues also arise from this layer. The next layer to appear after the hypoblast is the amnion, a layer of extraembryonic ectoderm that ultimately encloses the entire embryo in a fluid-filled chamber called the amniotic cavity (see Chapter 7).”
Implantation is the process of the blastocyst embedding into the endometrial lining of the uterus, which typically occurs in Week 2 of development. For implantation to occur, the blastocyst must completely hatch from the zona pellucida once the conceptus enters the uterine cavity. https://www.ncbi.nlm.nih.gov/books/NBK554562/
https://pubmed.ncbi.nlm.nih.gov/32310425/ The yolk sac, or umbilical vesicle, is a small membranous structure outside the embryo with various functions during embryonic development. The yolk sac reduces in size, communicates ventrally with the developing embryo via the yolk stalk, and later regresses.
Legier, T., Rattier, D., Llewellyn, J. et al.Epithelial disruption drives mesendoderm differentiation in human pluripotent stem cells by enabling TGF-β protein sensing.Nat Commun14, 349 (2023). https://doi.org/10.1038/s41467-023-35965-8
尾芽 tail budと第2次神経誘導
Fate of the Primitive Streak, Teratomas, formation of the Notochord, Diastematomyelia, Chordoma, + Douglas Gillard, DC, Professor of Clinical Science チャンネル登録者数 6.49万人
The extraembryonic coelom, also called the chorionic cavity, is continuous with the intraembryonic coelomalong the lateral edge of the embryo, where the lateral plate mesoderm has split into splanchnopleuric and somatopleuric layers.
After complete resection, a small but significant survival benefit has been seen with platinum-basedadjuvant chemotherapy 補助化学療法 for patients with stage II to IIIA disease.
As adjuvant therapy 補助療法, first-generation EGFR-TKIs are not associated with a survival benefit among patients with NSCLC who have EGFR wild-type or amplified tumors.
The EVAN trial showed a longer disease-free survival at 2 years with adjuvanterlotinib than with chemotherapy among patients with EGFR mutation–positive stage IIIA tumors.
In the ADJUVANT/CTONG1104 trial involving patients with stage II to IIIA EGFR mutation–positive NSCLC, the median disease-free survival among patients in the intention-to-treat population who received adjuvant gefitinib was significantly longer than that among patients who received chemotherapy and disease-free survival was higher at 3 years, although this benefit did not translate to an overall survival advantage.
Wu and colleagues now report in the Journal the results of the phase 3, double-blind, randomized ADAURA trial of osimertinib as adjuvant therapy administered for 3 years after complete resection in patients with stage IB to IIIA EGFR mutation–positive NSCLC.
EGFR-TKIs plus chemotherapy are currently being studied as neoadjuvant therapy in patients with EGFR mutation–positive stage II to IIIB disease and as first-line therapy in patients with EGFR mutation–positive metastatic disease. https://www.nejm.org/doi/full/10.1056/NEJMe2029532
