The C. elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14 Rosalind C. Lee ,Rhonda L. Feinbaum and Victor Ambros https://www.sciencedirect.com/science/article/pii/009286749390529Y?via%3Dihub
Posttranscriptional regulation of the heterochronic gene lin-14 by lin-4 mediates temporal pattern formation in C. elegans Bruce Wightman, Ilho Ha, Gary Ruvkun Volume 75, Issue 5 , 3 December 1993, Pages 855-862 Cell https://www.sciencedirect.com/science/article/pii/0092867493905304
Conservation of the sequence and temporal expression of let-7 heterochronic regulatory RNANature volume 408, pages86–89 (2000) Published: 02 November 2000
ヒトのマイクロRNA
The chromosome 19 miRNA cluster (C19MC) is the largest human miRNA gene cluster, comprising roughly 8% of all known human miRNA genes, and is exclusively expressed in the placenta and in undifferentiated cells
MicroRNAs (miRNAs) are endogenous, 19–24 nucleotide, non-coding RNAs that post-transcriptionally regulate gene expression through sequence-specific base-pairing with target mRNAs.
In the human placenta, miRNAs are synthesized and expressed primarily in trophoblasts.
This primate-specific miRNA cluster spans ∼100 kb at human chromosome 19q13.41, and spans 46 miRNA genes
In the human placenta, the C19MC cluster is imprinted, and is exclusively expressed from the paternally inherited allele
Aberrant expression of C19MC miRNAs is observed in specific human malignancies, where they may contribute to tumor invasiveness (Li et al., 2009; Rippe et al., 2010).
The expression profile of C19MC microRNAs in primary human trophoblast cells and exosomesMol Hum Reprod. 2012 Aug; 18(8): 417–424. Published online 2012 Feb 29. doi: 10.1093/molehr/gas013 PMCID: PMC3389496 PMID: 22383544
Selective activation of miRNAs of the primate-specific chromosome 19 miRNA cluster (C19MC) in cancer and stem cells and possible contribution to regulation of apoptosis Phan Nguyen Nhi Nguyen, Chiu-Jung Huang, Shigeki Sugii, Soon Keng Cheong & Kong Bung Choo Journal of Biomedical Science volume 24, Article number: 20 (2017) https://jbiomedsci.biomedcentral.com/articles/10.1186/s12929-017-0326-z
C19MC MicroRNAs Regulate the Migration of Human Trophoblasts Endocrinology. 2014 Dec; 155(12): 4975–4985. Published online 2014 Sep 11. doi: 10.1210/en.2014-1501 PMCID: PMC4239420 PMID: 25211593
The expression profile of C19MC microRNAs in primary human trophoblast cells and exosomesMol Hum Reprod. 2012 Aug; 18(8): 417–424. Published online 2012 Feb 29. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3389496/
胎盤とマイクロRNA
Placental trophoblast cell-derived exosomal microRNA-1290 promotes the interaction between endometrium and embryo by targeting LHX6 Nucleic Acids Volume 26 , 3 December 2021, Pages 760-772
Imprinted MicroRNA Gene Clusters in the Evolution, Development, and Functions of Mammalian Placenta REVIEW article Front. Genet., 18 January 2019 Sec. RNA Volume 9 – 2018 | https://doi.org/10.3389/fgene.2018.00706 https://www.frontiersin.org/journals/genetics/articles/10.3389/fgene.2018.00706/full
The Fibroblast Growth Factor signaling pathway First published: 13 March 2015 https://wires.onlinelibrary.wiley.com/doi/10.1002/wdev.176
From Cradle to Grave: The Multiple Roles of Fibroblast Growth Factors in Neural Development Neuron Volume 71, Issue 4 , 25 August 2011, Pages 574-588 https://www.sciencedirect.com/science/article/pii/S0896627311006787
Life Unfoldingを読んでいたら、FGFが進化の過程で繰り返し異なる器官の発生に使われたという記述があり、進化の順に、膵臓 pancreas、肺 lung、前立腺 prostateが挙げられていました。ChatGPTで進化の順を確認してみます。
Pancreas (Appeared First)
The pancreas is one of the earliest organs to appear in evolutionary history. It evolved as part of the digestive system in early vertebrates.
The pancreas or pancreas-like organs are found in jawed vertebrates (gnathostomes) and even in some jawless vertebrates (agnathans). Its dual function as both an endocrine (hormone production) and exocrine (enzyme secretion) organ suggests its ancient origin.
Estimated Appearance: Over 400 million years ago, in the early vertebrates.
Lung (Second)
Lungs evolved later, initially appearing as primitive respiratory structures in early fish that inhabited oxygen-poor waters. This structure was likely a precursor to both lungs and swim bladders in fish.
The development of lungs was crucial for the transition of vertebrates to terrestrial life. Primitive lungs are thought to have evolved before the Devonian period, approximately 400 million years ago.
Estimated Appearance: Approximately 400 million years ago, but after the pancreas.
Prostate (Appeared Last)
The prostate gland is a more recent evolutionary development and is specific to mammals. It is part of the male reproductive system, responsible for producing seminal fluid components.
Prostate evolution is linked to the diversification of reproductive strategies in mammals, and it is absent in more primitive vertebrates such as reptiles and amphibians.
Estimated Appearance: Roughly 200-250 million years ago, coinciding with early mammals.
Fgf10/Fgfr2b Signaling Orchestrates the Symphony of Molecular, Cellular, and Physical Processes Required for Harmonious Airway Branching Morphogenesis Front. Cell Dev. Biol., 12 January 2021 Sec. Cell Growth and Division Volume 8 – 2020 | https://doi.org/10.3389/fcell.2020.620667
FGF18 promotes human lung branching morphogenesis through regulating mesenchymal progenitor cells 17 Mar 2023 https://doi.org/10.1152/ajplung.00316.2022
Fibroblast Growth Factor 10 (FGF10) and branching morphogenesis in the embryonic mouse lung Development (1997) 124 (23): 4867–4878. https://doi.org/10.1242/dev.124.23.4867
Fibroblast growth factors (FGFs) can play a role in the branching morphogenesis of the ureteric bud (UB). FGF2 and FGF7 are two FGFs that have been shown to have different effects on UB branching:
FGF2: Induces the formation of globular structures with an irregular branching pattern
FGF7: A more potent stimulator of UB growth
Other factors that may be involved in UB branching include: GDNF and A BSN-derived factor(s).
The UB is an epithelial tube that originates from the nephric duct and branches repeatedly to form the renal collecting duct system. Defects in UB growth and branching can lead to renal agenesis, hypodysplasia, and other congenital abnormalities of the kidney and urinary tract.
The FGF system is associated with several downstream signaling pathways, including the RAS/mitogen-activating protein (MAP) kinase pathway, the phosphoinositide 3 (PI3) kinase/AKT pathway, and the phospholipase C gamma (PLCγ) pathway.
Multiple fibroblast growth factors support growth of the ureteric bud but have different effects on branching morphogenesis Mechanisms of Development Volume 109, Issue 2 , December 2001, Pages 123-135 https://www.sciencedirect.com/science/article/pii/S0925477301005925
線維芽細胞成長因子（FGF）と唾液腺の分岐形成
FGF signaling regulates salivary gland branching morphogenesis by modulating cell adhesion Development. 2023 Mar 15; 150(6): dev201293. Published online 2023 Mar 20. doi: 10.1242/dev.201293 PMCID: PMC10112918 PMID: 36861436 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10112918/
Signaling pathways regulating the branching of the Drosophila tracheal system.
a, The anterior-posterior and dorsal-ventral patterning genes induce bnl expression in mesenchymal cell clusters, which secrete and form a gradient of Bnl (green). Bnl induces btl expression (red) in the epithelial cells of the tracheal placodes that are closest to the Bnl source, and acts as a chemoattractant. The migrating cells coalesce into a primary branch.
b, Bnl induces secondary branch tip-cell genes in epithelial cells sensing the highest Bnl signal, which then suppress tip-cell gene expression in stalk cells via Notch signaling. Pointed is a pivotal tip-cell gene which upregulates MAPK signaling and Sprouty expression. Sprouty forms a negative-feedback loop by inhibiting Btl signaling.
c, Hypoxia induces local expression of bnl via Fatiga, leading to Btl signaling via Pointed and Blistered and resulting in terminal branch sprouting.
The role of the Notch signaling pathway in Drosophila development has been studied since a dominant notched wing phenotype was first reported in 1914, but its role in human development and disease has only been recognized since 1991, when mutations in NOTCH1 were associated with a form of T-cell acute lymphoblastic leukemia (T-ALL) [1]. In 1996, NOTCH3 mutations were found to cause CADASIL, a disorder characterized by stroke and dementia, with onset in the 3rd or 4th decade [2].
Understanding the Principles of Pattern Formation Driven by Notch Signaling by Integrating Experiments and Theoretical Models Front Physiol. 2020; 11: 929. Published online 2020 Jul 31. doi: 10.3389/fphys.2020.00929 PMCID: PMC7411240 PMID: 32848867
Neural progenitors are polarised along the apico-basal axis of the neuroepithelium and localise apical polarity proteins such as Pard3 to the apical surface. Most neural progenitors divide at the apical surface of the neuroepithelium. A daughter that inherits the apical attachment (outlined by Pard3), inherits the Delta modulator Mindbomb and is likely to become a neuron.
Delta-Notch Signaling: The Long and the Short of a Neuron’s Influence on Progenitor Fates J Dev Biol. 2020 Jun; 8(2): 8. Published online 2020 Mar 26. doi: 10.3390/jdb8020008 PMCID: PMC7345741 PMID: 32225077 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7345741/
Enhanced Delta-Notch Lateral Inhibition Model Incorporating Intracellular Notch Heterogeneity and Tension-Dependent Rate of Delta-Notch Binding that Reproduces Sprouting Angiogenesis Patterns Yen Ling Koon, Songjing Zhang, Muhammad Bakhait Rahmat, Cheng Gee Koh & Keng-Hwee Chiam Scientific Reports volume 8, Article number: 9519 (2018) Published: 22 June 2018 https://www.nature.com/articles/s41598-018-27645-1
Cis-interactions between Notch and Delta generate mutually exclusive signalling states David Sprinzak, Amit Lakhanpal, Lauren LeBon, Leah A. Santat, Michelle E. Fontes, Graham A. Anderson, Jordi Garcia-Ojalvo & Michael B. Elowitz Nature volume 465, pages86–90 (2010) Published: 25 April 2010 https://www.nature.com/articles/nature08959
Yes, that’s correct! The recipient cells of Sonic Hedgehog (Shh) signals are generally ciliated, as cilia are crucial for proper Shh signaling transduction. In vertebrates, the primary cilium is essential for Shh signaling because it serves as a compartment where key signaling components, like the receptors Patched (Ptch) and Smoothened (Smo), are localized and activated.
Here’s a bit more detail on the process:
Shh Binding to Patched (Ptch): In the absence of Shh, Ptch inhibits Smoothened (Smo), keeping it out of the cilia. When Shh binds to Ptch, this inhibition is relieved.
Smoothened Translocation to Cilia: With Ptch inhibition lifted, Smo moves into the cilia. This movement initiates downstream signaling, which eventually leads to the activation of Gli transcription factors and influences gene expression.
Role of Cilia: The cilium acts as a signaling hub in this process. Cells lacking primary cilia or with defective ciliary function are typically unable to transduce Shh signals effectively, underscoring the importance of cilia in Shh pathway activation.
Since primary cilia are a feature of most epithelial cells, it’s often these ciliated cells that can respond to Shh signaling. However, ciliated cells are not limited to epithelial tissues; some types of neuronal cells, for example, also have primary cilia and can respond to Shh signaling.
SHh-mediated transduction is initiated via extracellular SHh ligand binding to the 12-span transmembrane receptor, PATCHED-1 (PTCH-1) or the redundant receptor PTCH-2, in target cells (9, 10). In the absence of SHh, PTCH-1 and, redundantly, PTCH-2, catalytically inhibit downstream signaling activity with seven-transmembrane G-protein-coupled receptor, Smoothened (SMO) (11–13). Upon SHh binding to PTCH, the inhibitory interaction is terminated through internalization of PTCH, releasing SMO and allowing for phosphorylation to transduce signal into the cytoplasm (14). The resultant signal leads to the component dissociation of a large protein complex comprising of Sufu and GLIs in the cytoplasm, releasing the GLI transcription factors. Finally, the released GLI transcription factors translocate into the nucleus to execute transcriptional activation of specific target genes (15). https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2021.673154/full
After secretion into the extracellular milieu, the 20-kDa domain binds to a transmembrane receptor called patched. In the absence of Shh protein, patched interacts with and inhibits another transmembrane signaling protein called smoothened, repressing the expression of smoothened target genes. In contrast, in the presence of Shh protein, smoothened is no longer inhibited. Instead, it is transported into a primary (non-motile) cilium projecting from the cell’s surface, where it accumulates in the cilium’s cell membrane. This activates an intracellular signaling cascade that results in transcriptional activation of target genes. It is interesting to note that smoothened signaling in mammals involves three proteins (called Gli proteins) that function as transcriptional activators or repressors. These proteins are orthologs of the Drosophila Ci, or cubitus interruptus protein. When Shh is absent, Gli2 and Gli3 are cleaved and act as transcriptional repressors (GliR). When Shh is present, this proteolytic cleavage is inhibited, and Gli2, 3, and Gli1, which is induced in response to Shh signaling, act as transcriptional activators (GliA). The levels (concentration) of Shh determine the ratio of GliA versus GliR in a cell, which in turn determines the fate of that cell (see Fig. 5.19B).
Yes, in the presence of Shh signaling, Gli1 expression is primarily induced by Gli2 acting as an activator. Here’s how it works:
Shh Signal Activation: When Shh binds to Ptch, it relieves inhibition on Smoothened (Smo), allowing it to move into the cilia. This initiates downstream signaling events that lead to activation of Gli proteins.
Role of Gli2 as an Activator: Gli2 is the main transcriptional activator in the Shh pathway. In response to Shh signaling, Gli2 is stabilized and accumulates in its active form, which then translocates to the nucleus to drive the transcription of Shh target genes, including Gli1. Therefore, Gli2 is crucial for inducing Gli1 expression in Shh-responding cells.
Gli3 as a Repressor: Gli3 predominantly functions as a repressor in the absence of Shh signaling. Without Shh, Gli3 is processed into a repressor form that inhibits target gene expression. In the presence of Shh, Gli3 processing into its repressor form is inhibited, allowing the pathway to activate Gli1 and other target genes through Gli2.
Gli1 as an Amplifier: Interestingly, Gli1 itself doesn’t act as an initial activator but rather serves as an amplifier of Shh signaling. Once expressed, Gli1 provides positive feedback, reinforcing the activation of Shh target genes.
In summary, Gli2 is the primary inducer of Gli1 expression when Shh signaling is active, with Gli1 serving to further amplify the pathway’s response.
身長と体重が平均的な女性よりも大きくなります。また、腋毛axillary hairや陰毛 public hair は、乏しいか無毛になります。これは体毛の発育がアンドロゲン受容体に依存するためです。また、膣の長さは通常より短く、盲端（blind)になっています。
A shortened blind-ending vagina is observed in almost all patients and the vaginal measurement varied from 2.5 to 8 cm in CAIS and 1.5 – 4 cm in PAIS.
Pubic and axillary hair are sparse or absent (1,14).
Final height in CAIS is above normal mean female height, probably due to the action of the growth-controlling gene (GCY) located at the Y chromosome (15).
newborns with CAIS have the same size of male newborns
the final height of CAIS individuals (165.7 ± 8.9 cm) was taller than described for Brazilian females, but lower than expected for Brazilian males (15).
