Molecular Development: Difference between revisions
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* '''Key role for CTCF in establishing chromatin structure in human embryos'''{{#pmid:31801998|PMID31801998}} "In the interphase of the cell cycle, chromatin is arranged in a hierarchical structure within the nucleus1,2, which has an important role in regulating gene expression3-6. However, the dynamics of 3D chromatin structure during human embryogenesis remains unknown. Here we report that, unlike mouse sperm, human sperm cells do not express the chromatin regulator CTCF and their chromatin does not contain topologically associating domains (TADs). Following human fertilization, TAD structure is gradually established during embryonic development. In addition, A/B compartmentalization is lost in human embryos at the 2-cell stage and is re-established during embryogenesis. Notably, blocking zygotic genome activation (ZGA) can inhibit TAD establishment in human embryos but not in mouse or Drosophila. Of note, CTCF is expressed at very low levels before ZGA, and is then highly expressed at the ZGA stage when TADs are observed. TAD organization is significantly reduced in CTCF knockdown embryos, suggesting that TAD establishment during ZGA in human embryos requires CTCF expression. Our results indicate that CTCF has a key role in the establishment of 3D chromatin structure during human embryogenesis." | |||
* '''Transcriptional control of lung alveolar type 1 cell development and maintenance by NK homeobox 2-1'''{{#pmid:31548395|PMID31548395}} "The extraordinarily thin alveolar type 1 (AT1) cell constitutes nearly the entire gas exchange surface and allows passive diffusion of oxygen into the blood stream. Despite such an essential role, the transcriptional network controlling AT1 cells remains unclear. Using cell-specific knockout mouse models, genomic profiling, and 3D imaging, we found that NK homeobox 2-1 (Nkx2-1) is expressed in AT1 cells and is required for the development and maintenance of AT1 cells. Without Nkx2-1, developing AT1 cells lose 3 defining features-molecular markers, expansive morphology, and cellular quiescence-leading to alveolar simplification and lethality. NKX2-1 is also cell-autonomously required for the same 3 defining features in mature AT1 cells. Intriguingly, Nkx2-1 mutant AT1 cells activate gastrointestinal (GI) genes and form dense microvilli-like structures apically. Single-cell RNA-seq supports a linear transformation of Nkx2-1 mutant AT1 cells toward a GI fate. Whole lung ChIP-seq shows NKX2-1 binding to 68% of genes that are down-regulated upon Nkx2-1 deletion, including 93% of known AT1 genes, but near-background binding to up-regulated genes. Our results place NKX2-1 at the top of the AT1 cell transcriptional hierarchy and demonstrate remarkable plasticity of an otherwise terminally differentiated cell type. {{respiratory}} | * '''Transcriptional control of lung alveolar type 1 cell development and maintenance by NK homeobox 2-1'''{{#pmid:31548395|PMID31548395}} "The extraordinarily thin alveolar type 1 (AT1) cell constitutes nearly the entire gas exchange surface and allows passive diffusion of oxygen into the blood stream. Despite such an essential role, the transcriptional network controlling AT1 cells remains unclear. Using cell-specific knockout mouse models, genomic profiling, and 3D imaging, we found that NK homeobox 2-1 (Nkx2-1) is expressed in AT1 cells and is required for the development and maintenance of AT1 cells. Without Nkx2-1, developing AT1 cells lose 3 defining features-molecular markers, expansive morphology, and cellular quiescence-leading to alveolar simplification and lethality. NKX2-1 is also cell-autonomously required for the same 3 defining features in mature AT1 cells. Intriguingly, Nkx2-1 mutant AT1 cells activate gastrointestinal (GI) genes and form dense microvilli-like structures apically. Single-cell RNA-seq supports a linear transformation of Nkx2-1 mutant AT1 cells toward a GI fate. Whole lung ChIP-seq shows NKX2-1 binding to 68% of genes that are down-regulated upon Nkx2-1 deletion, including 93% of known AT1 genes, but near-background binding to up-regulated genes. Our results place NKX2-1 at the top of the AT1 cell transcriptional hierarchy and demonstrate remarkable plasticity of an otherwise terminally differentiated cell type. {{respiratory}} | ||
Revision as of 07:47, 13 December 2019
Embryology - 10 Jun 2024 Expand to Translate |
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Introduction
This page is a link to many different resources related to molecular development. I am 2.85 billion nucleotides of DNA, but so is a chimpanzee, and all this DNA encodes only about 20,000-25,000 protein-coding genes. In development, I am not that different from a mouse or a fly and many of the signals that regulate development are used time and time again.
We have come a long way from just observing development to now wanting to understand how the complex program of development is controlled. Using new research tools and some excellent animal models researchers have discovered common themes and mechanisms that tie all embryonic development together.
What is remarkable, given our biological diversity, is the strong evolutionary conservation of developmental mechanisms. This has been a boon in allowing the use of many (easier) model systems such as the genetist's tool the fruitfly, and the worm, frog, chicken, zebrafish and mouse (see Animal Development page).
Gene Regulatory Network (GRN) is a set of genes, or parts of genes, that interact with each other to control a specific cell function. In the embryo, these are the molecular mechanisms/pathways used in the development and differentiation of specific cell types and tissues.
A continuing theme also seems to be the reuse of signals at different times and places within the embryo, for diiferent jobs. This has given rise to the concept of "switches" which by themselves may contain no "information" but to activate other genes or switches. Finally, you can imagine that of our 20,000-25,000 protein-coding genes, a large number of these may only be expressed during development or if reused, have a completely different role in the mature animal. The new field of epigenetics has also begun to florish with some recent important findings.
Molecular mechanisms of development is an exciting area and requires a variety of different skills. This page introduces only a few examples and should give you a feel for the topic. Note that each section of system notes has a page covering molecular development in that system. I have included information about the basic building blocks of proteins (amino acids).
Hox Genes | |
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Fly wild-type head[2] | Fly antennapedia mutant head[2] |
Factor Links: AMH | hCG | BMP | sonic hedgehog | bHLH | HOX | FGF | FOX | Hippo | LIM | Nanog | NGF | Nodal | Notch | PAX | retinoic acid | SIX | Slit2/Robo1 | SOX | TBX | TGF-beta | VEGF | WNT | Category:Molecular |
Mechanism Links: mitosis | cell migration | cell junctions |epithelial invagination | epithelial mesenchymal transition | mesenchymal epithelial transition | epithelial mesenchymal interaction | morphodynamics | tube formation | apoptosis | autophagy | axes formation | time | molecular |
- Molecular System Links: Heart | Neural | Renal | Respiratory | Mechanisms | Factors | Molecular
Some Recent Findings
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Older papers |
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These papers originally appeared in the Some Recent Findings table, but as that list grew in length have now been shuffled down to this collapsible table.
See also the Discussion Page for other references listed by year and References on this current page.
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Movies
Translation |
Page | Play |
Starting Out
There are several different ways to begin to look at molecular development.
- look at the earliest molecular events involved in patterning the differentiation of cells- axis formation.
- or look at early events in patterning with differentiation and migration of cells to form the trilaminar embryo (gastrulation).
- or look at the signaling mechanisms and the different types of factors involved.
- or look at their role in the development of specific systems.
Signaling during development, though complex, can also be grouped into a few specific classes. These mechanisms have also been listed and described briefly on Signaling Mechanisms page.
For this section, Molecular Biology of the Cell (now indexed and available online from PubMed) and the extracted Cell Biology version are good reference texts. Also the key journals in this area are: Development, Genes and Development, PNAS, EMBOJ.
There is also detailed molecular information available from the abnormalities pages where there are links to the OMIM Database entry for specific genetic disorders.
Gene Expression
DNA -> RNA -> Protein
Our genetic information is stored within each cell in cell organelles of the nucleus and mitochondria.
- In the nucleus as chromosomes.
- In the mitochondria as circular DNA.
Gene expression can often simply be described by the pathway: DNA -> mRNA -> Protein. While each cell contains the same genetic material, not all genes are ever expressed and the subset of genes expressed at any one time affects cellular differentiation and mature cell function. This can be impacted by both signaling and epigenetic mechanisms.
The human chromosomes consist of proteins and nucleic acids, the common nucleic acids or bases that forms DNA can be represented by a standardised IUPAC single letter code.
Deoxyribonucleic acid
Deoxyribonucleic acid (DNA) consists of 4 nucleotides (bases):
- Adenine (A)
- Cytosine (C)
- Guanine (G)
- Thymine (T)
An additional amino acid, 5-Formylcytosine (5fC), a rare nucleotide has recently been identified as a stable DNA modification occurring in mammals.[9] The function of this additional base was thought to be involved only in active DNA demethylation, but may also have roles in gene regulation.
Ribonucleic acid
Ribonucleic acid (RNA) consists of 4 nucleotides:
- Adenine (A)
- Cytosine (C)
- Guanine (G)
- Uracil (U)
The original "RNA family" consisted of just 3 main members; transfer RNA (tRNA), ribosomal RNA (rRNA) and messenger RNAs (mRNA). Involved in gene expression through protein translation (synthesis).
In recent years this RNA family, shown in the table below, has been expanded to include newly identified members: small nuclear RNA (snRNA) , small nucleolar RNA (snoRNA), and short regulatory RNA (piwi-associated RNA (piRNA), endogenous short-interfering RNA (endo-siRNA) and microRNA (miRNA) and now long non-coding RNA (lncRNA). Each of these new family members has a range of potential roles in development and differentiation.
RNA Class | Acronym | Roles | Examples | Reviews |
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transfer RNA | tRNA | carry amino acid in cell cytoplasm to ribosome | PMID 24966867 PMID 27095039 | |
messenger RNA | mRNA | transcribed from DNA in cell nucleus and relocate to cytoplasm for translation on the ribosome | Example | PMID 28102265 |
ribosomal RNA | rRNA | structural RNA that allow the assembly of ribosomal proteins in the cytoplasm into ribosomal subunits required for protein translation | Example | PMID 30356013 |
small nuclear RNA | snRNA | involved in cell nucleus RNA splicing | PMID 23980890 | |
small nucleolar RNA | snoRNA | modify other small RNAs (rRNAs and tRNAs) | box C/D snoRNAs and the box H/ACA | PMID 21664409 PMID 19446021 |
microRNA | miRNA | post-transcriptional regulator of gene expression | PMID 25128264 | |
endogenous short-interfering RNA | endo-siRNA | short regulatory RNA | mainly characterised in plants | PMID 22578318 |
piwi-associated RNA | piRNA | short regulatory RNA | PMID 18032451 PMID 22103557 | |
long non-coding RNA | ncRNA | non-coding RNA greater than 200bp in length may have different roles in signalling, protein processing and differentiation | PMID 24829860 |
Protein
The individual amino acids that form all proteins can be represented by a standardised single letter code, or three letter code or by their entire name.
Single Letter Code
A - Alanine (Ala) | C - Cysteine (Cys) | D - Aspartic Acid (Asp) | E - Glutamic Acid (Glu) | F - Phenylalanine (Phe) | G - Glycine (Gly) | H - Histidine (His) | I - Isoleucine (Ile) | K - Lysine (Lys) |L - Leucine (Leu) | M - Methionine (Met) | N - Asparagine (Asn) | P - Proline (Pro) | Q - Glutamine (Gln) | R - Arginine (Arg) | S - Serine (Ser) | T - Threonine (Thr) | V - Valine (Val) | W - Tryptophan (Trp) | Y - Tyrosine (Tyr)
Amino Acid | 3-Letter | 1-Letter | Side chain polarity | Side chain acidity or basicity of neutral species | Hydropathy index |
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Alanine | Ala | A | nonpolar | neutral | 1.8 |
Arginine | Arg | R | polar | basic (strongly) | -4.5 |
Asparagine | Asn | N | polar | neutral | -3.5 |
Aspartic acid | Asp | D | polar | acidic | -3.5 |
Cysteine | Cys | C | polar | neutral | 2.5 |
Glutamic acid | Glu | E | polar | acidic | -3.5 |
Glutamine | Gln | Q | polar | neutral | -3.5 |
Glycine | Gly | G | nonpolar | neutral | -0.4 |
Histidine | His | H | polar | basic (weakly) | -3.2 |
Isoleucine | Ile | I | nonpolar | neutral | 4.5 |
Leucine | Leu | L | nonpolar | neutral | 3.8 |
Lysine | Lys | K | polar | basic | -3.9 |
Methionine | Met | M | nonpolar | neutral | 1.9 |
Phenylalanine | Phe | F | nonpolar | neutral | 2.8 |
Proline | Pro | P | nonpolar | neutral | -1.6 |
Serine | Ser | S | polar | neutral | -0.8 |
Threonine | Thr | T | polar | neutral | -0.7 |
Tryptophan | Trp | W | nonpolar | neutral | -0.9 |
Tyrosine | Tyr | Y | polar | neutral | -1.3 |
Valine | Val | V | nonpolar | neutral | 4.2 |
Hydropathy Index
- a number representing the hydrophobic or hydrophilic properties of the amino acid sidechain.
- larger the number the more hydrophobic the amino acid.
- most hydrophobic amino acids are isoleucine (4.5) and valine (4.2), hydrophobic amino acids tend to be internal
- most hydrophilic amino acids are arginine (-4.5) and lysine (-3.9), hydrophilic amino acids are more commonly found towards the protein surface.
- Links: Protein
Signaling Factors
Hedgehog signaling pathway[11]
Note spelling difference: USA signaling, UK signalling.
Factor Links: AMH | hCG | BMP | sonic hedgehog | bHLH | HOX | FGF | FOX | Hippo | LIM | Nanog | NGF | Nodal | Notch | PAX | retinoic acid | SIX | Slit2/Robo1 | SOX | TBX | TGF-beta | VEGF | WNT | Category:Molecular |
Axis Formation
Embryo left-right asymmetry pathway[12]
The mechanisms that specify location within the embryo, therefore establishing axes, appears to be controlled by similar signaling mechanisms in different species.
- Links: Axis Formation
Transcription Factors
Transcription factors act by activating or inhibiting transcription either a single gene or more commonly acting on a family of genes. The transcription factor binding sites can be upstream of affected genes or some distance away from the initiation codon and many of these individual factors belong to families of many factors that share common DNA binding motifs.
- forkhead box (FOX) superfamily contain a DNA-binding motif known as the forkhead box or winged-helix domain.
Epigenetics
Epigenetics as the name implies, is the inheritance mechanisms that lie outside the DNA sequence of our genes.
One of the initial discoveries was the effects of DNA methylation upon gene expression and then modifications of nucleosomal histones. This DNA methylation, usually associated with 5-methylcytosine (m5C), leads to transcriptional silencing in vertebrates.
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References
- ↑ Qiu J. (2006). Epigenetics: unfinished symphony. Nature , 441, 143-5. PMID: 16688142 DOI.
- ↑ 2.0 2.1 Turner FR & Mahowald AP. (1979). Scanning electron microscopy of Drosophila melanogaster embryogenesis. III. Formation of the head and caudal segments. Dev. Biol. , 68, 96-109. PMID: 108157
- ↑ Chen X, Ke Y, Wu K, Zhao H, Sun Y, Gao L, Liu Z, Zhang J, Tao W, Hou Z, Liu H, Liu J & Chen ZJ. (2019). Key role for CTCF in establishing chromatin structure in human embryos. Nature , , . PMID: 31801998 DOI.
- ↑ Little DR, Gerner-Mauro KN, Flodby P, Crandall ED, Borok Z, Akiyama H, Kimura S, Ostrin EJ & Chen J. (2019). Transcriptional control of lung alveolar type 1 cell development and maintenance by NK homeobox 2-1. Proc. Natl. Acad. Sci. U.S.A. , 116, 20545-20555. PMID: 31548395 DOI.
- ↑ Langen UH, Pitulescu ME, Kim JM, Enriquez-Gasca R, Sivaraj KK, Kusumbe AP, Singh A, Di Russo J, Bixel MG, Zhou B, Sorokin L, Vaquerizas JM & Adams RH. (2017). Cell-matrix signals specify bone endothelial cells during developmental osteogenesis. Nat. Cell Biol. , 19, 189-201. PMID: 28218908 DOI.
- ↑ Nishimura T, Sato T, Yamamoto Y, Watakabe I, Ohkawa Y, Suyama M, Kobayashi S & Tanaka M. (2015). Sex determination. foxl3 is a germ cell-intrinsic factor involved in sperm-egg fate decision in medaka. Science , 349, 328-31. PMID: 26067255 DOI.
- ↑ Davidson EH & Levine MS. (2008). Properties of developmental gene regulatory networks. Proc. Natl. Acad. Sci. U.S.A. , 105, 20063-6. PMID: 19104053 DOI.
- ↑ Nahmad M & Stathopoulos A. (2009). Dynamic interpretation of hedgehog signaling in the Drosophila wing disc. PLoS Biol. , 7, e1000202. PMID: 19787036 DOI.
- ↑ Martin Bachman, Santiago Uribe-Lewis, Xiaoping Yang, Heather E Burgess, Mario Iurlaro, Wolf Reik, Adele Murrell and Shankar Balasubramanian. 5-Formylcytosine can be a stable DNA modification in mammals Nature Chemical Biology (2015) doi:10.1038/nchembio.1848.
- ↑ <pubmed>7108955</pubmed>
- ↑ Bürglin TR. (2008). The Hedgehog protein family. Genome Biol. , 9, 241. PMID: 19040769 DOI.
- ↑ Norris DP. (2012). Cilia, calcium and the basis of left-right asymmetry. BMC Biol. , 10, 102. PMID: 23256866 DOI.
Terms
Genetic Terms (expand to view) | ||
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genetic abnormalities | Molecular Development | meiosis | mitosis
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External Links
External Links Notice - The dynamic nature of the internet may mean that some of these listed links may no longer function. If the link no longer works search the web with the link text or name. Links to any external commercial sites are provided for information purposes only and should never be considered an endorsement. UNSW Embryology is provided as an educational resource with no clinical information or commercial affiliation.
Gene Ontology Consortium
- Gene Ontology Consortium - "The mission of the GO Consortium is to develop a comprehensive, computational model of biological systems, ranging from the molecular to the organism level, across the multiplicity of species in the tree of life."
- NHGR - The ENCODE Project ENCyclopedia Of DNA Elements
- Foldit - Amino Acids
- Cytoscape - open source software platform for visualizing complex networks and integrating these with any type of attribute data.
- iRegulon - Detects master regulators and cis-regulatory interactions.
Glossary Links
- Glossary: A | B | C | D | E | F | G | H | I | J | K | L | M | N | O | P | Q | R | S | T | U | V | W | X | Y | Z | Numbers | Symbols | Term Link
Cite this page: Hill, M.A. (2024, June 10) Embryology Molecular Development. Retrieved from https://embryology.med.unsw.edu.au/embryology/index.php/Molecular_Development
- © Dr Mark Hill 2024, UNSW Embryology ISBN: 978 0 7334 2609 4 - UNSW CRICOS Provider Code No. 00098G