Molecular Development

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Introduction

Amphibian oocyte transcription
Epigenetics mechanisms[1]

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).


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.


In terms of molecular mechanisms, the field of epigenetics has 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).


Molecular Links: Introduction | Genetics | Epigenetics | Mitosis | Meiosis | X Inactivation | Signaling | Factors | Mouse Knockout | microRNA | Mechanisms | Developmental Enhancers | Protein | Genetic Abnormal | Category:Molecular
Historic Embryology  
Morgan1925.jpg By Morgan, T. H. (1925). Evolution and genetics. Princeton: Princeton University Press.

Morgan (1925) Evolution and Genetics: 1 Different Kinds of Evolution | 2 Four Great Historical Speculations | 3 Evidence for Organic Evolution | 4 Materials of Evolution | 5 Mendel's Two Laws of Heredity | 6 Chromosomes and Mendel’s Two Laws | 7 Linkage Groups and the Chromosomes | 8 Sex-Linked Inheritance | 9 Crossing-over | 10 Natural Selection and Evolution | 11 Origin of Species by Natural Selection | 12 Non-Inheritance of Acquired Characters | 13 Human Inheritance | Figures
Historic Disclaimer

Hox Genes
Fly wild-type head.jpg Fly antennapedia head.jpg
Fly wild-type head[2] Fly antennapedia mutant head[2]


Factor Links: hCG | BMP | Sonic hedgehog | HOX | FGF | Nanog | Nodal | Notch | FOX | PAX | Retinoic acid | SIX | Slit2/Robo1 | Sox | TBX | TGF-beta | VEGF | WNT | Hippo | Category:Molecular


Mechanism Links: Epithelial Invagination | Epithelial Mesenchymal Transition | Mesenchymal Epithelial Transition | Epithelial Mesenchymal Interaction | Cell Migration | Morphodynamics | Tube Formation | Apoptosis | Axes Formation | Molecular


Molecular System Links: Heart | Neural | Renal | Respiratory | Mechanisms | Factors | Molecular

Some Recent Findings

  • Cell-matrix signals (integrin β1) specify bone endothelial cells during developmental osteogenesis[3] “Blood vessels in the mammalian skeletal system control bone formation and support haematopoiesis by generating local niche environments. Here, we report that embryonic and early postnatal long bone contains a specialized endothelial cell subtype, termed type E, which strongly supports osteoblast lineage cells and later gives rise to other endothelial cell subpopulations. The differentiation and functional properties of bone endothelial cells require cell-matrix signalling interactions." Bone Development | INTEGRIN BETA-1
  • foxl3 is a germ cell-intrinsic factor involved in sperm-egg fate decision in medaka[4] "Sex determination is an essential step in the commitment of a germ cell to a sperm or egg. However, the intrinsic factors that determine the sexual fate of vertebrate germ cells are unknown. Here we show that foxl3, which is expressed in germ cells but not somatic cells in the gonad, is involved in sperm-egg fate decision in medaka fish. Adult XX medaka with disrupted foxl3 developed functional sperm in the expanded germinal epithelium of a histologically functional ovary. In chimeric medaka, mutant germ cells initiated spermatogenesis in female wild-type gonad. These results indicate that a germ cell-intrinsic cue for the sperm-egg fate decision is present in medaka and that spermatogenesis can proceed in a female gonadal environment." ( Forkhead Transcription Factor foxl3 is an ancient duplicated copy of foxl2 | Medaka Development | Oocyte Development | Spermatozoa Development)
  • The Encyclopedia of DNA Elements (ENCODE) project Wed, Sep 5, 2012 "The Human Genome Project produced an almost complete order of the 3 billion pairs of chemical letters in the DNA that embodies the human genetic code — but little about the way this blueprint works. Now, after a multi-year concerted effort by more than 440 researchers in 32 labs around the world, a more dynamic picture gives the first holistic view of how the human genome actually does its job." NIH Nature
  • Properties of developmental gene regulatory networks[5] Introductory paper from the "Gene Networks in Development and Evolution Special Feature Sackler Colloquium" (2008) "The modular components, or subcircuits, of developmental gene regulatory networks (GRNs) execute specific developmental functions, such as the specification of cell identity. We survey examples of such subcircuits and relate their structures to corresponding developmental functions. These relations transcend organisms and genes, as illustrated by the similar structures of the subcircuits controlling the specification of the mesectoderm in the Drosophila embryo and the endomesoderm in the sea urchin, even though the respective subcircuits are composed of nonorthologous regulatory genes."

Movies

MRNA translation icon.jpg
 ‎‎Translation
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Starting Out

Model of Sonic hedgehog signaling in the drosophila wing

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)

Cytosine and by-products structure.jpg

An additional amino acid, 5-Formylcytosine (5fC), a rare nucleotide has recently been identified as a stable DNA modification occurring in mammals.[6] 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
transfer RNA tRNA carry amino acid in cell cytoplasm to ribosome PMID 24966867
messenger RNA mRNA transcribed from DNA in cell nucleus and relocate to cytoplasm for translation on the ribosome Example
ribosomal RNA rRNA structural RNA that allow the assembly of ribosomal proteins in the cytoplasm into ribosomal subunits required for protein translation Example
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


Links: Molecular Development - Ribonucleic acid | microRNA

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

[7]

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[7]

  • 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.jpg

Hedgehog signaling pathway[8]

Note spelling difference: USA signaling, UK signalling.

Factor Links: hCG | BMP | Sonic hedgehog | HOX | FGF | Nanog | Nodal | Notch | FOX | PAX | Retinoic acid | SIX | Slit2/Robo1 | Sox | TBX | TGF-beta | VEGF | WNT | Hippo | Category:Molecular

Axis Formation

Embryo left-right asymmetry pathway.jpg

Embryo left-right asymmetry pathway[9]

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.

Links: Epigenetics
Epigenetics mechanisms

References

  1. Jane Qiu Epigenetics: unfinished symphony. Nature: 2006, 441(7090);143-5 PubMed 16688142
  2. 2.0 2.1 F R Turner, A P Mahowald Scanning electron microscopy of Drosophila melanogaster embryogenesis. III. Formation of the head and caudal segments. Dev. Biol.: 1979, 68(1);96-109 PubMed 108157
  3. Urs H Langen, Mara E Pitulescu, Jung Mo Kim, Rocio Enriquez-Gasca, Kishor K Sivaraj, Anjali P Kusumbe, Amit Singh, Jacopo Di Russo, M Gabriele Bixel, Bin Zhou, Lydia Sorokin, Juan M Vaquerizas, Ralf H Adams Cell-matrix signals specify bone endothelial cells during developmental osteogenesis. Nat. Cell Biol.: 2017, 19(3);189-201 PubMed 28218908
  4. Toshiya Nishimura, Tetsuya Sato, Yasuhiro Yamamoto, Ikuko Watakabe, Yasuyuki Ohkawa, Mikita Suyama, Satoru Kobayashi, Minoru Tanaka foxl3 is a germ cell-intrinsic factor involved in sperm-egg fate decision in medaka. Science: 2015; PubMed 26067255 | Science.
  5. Eric H Davidson, Michael S Levine Properties of developmental gene regulatory networks. Proc. Natl. Acad. Sci. U.S.A.: 2008, 105(51);20063-6 PubMed 19104053 | PNAS
  6. 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.
  7. 7.0 7.1 J Kyte, R F Doolittle A simple method for displaying the hydropathic character of a protein. J. Mol. Biol.: 1982, 157(1);105-32 PubMed 7108955
  8. Thomas R Bürglin The Hedgehog protein family. Genome Biol.: 2008, 9(11);241 PubMed 19040769 | PMC2614485 | Genome Biology
  9. Dominic P Norris Cilia, calcium and the basis of left-right asymmetry. BMC Biol.: 2012, 10;102 PubMed 23256866 | BMC Biology


Terms

Molecular Development

  • antisense - a sequence of DNA that is complementary usually to coding sequence of DNA or mRNA. Has been used experimentally to perturb or block gene expression. Also a mechanism that has been found to occur naturally as a regulatory mechanism.
  • autosomal inheritance - some hereditary diseases are described as autosomal which means that the disease is due to a DNA error in one of the 22 pairs that are not sex chromosomes. Both boys and girls can then inherit this error. If the error is in a sex chromosome, the inheritance is said to be sex-linked.
  • base - another term for nucleotide (usually a t c g).
  • base pair - Double stranded DNA has nucleotides A-T, C-G, paired by hydrogen bonds (2 for AT, 3 for GC). Note this means that GC is harder to separate that AT.
  • cis-acting elements - DNA sequences that through transcription factors or other trans-acting elements or factors, regulate the expression of genes on the same chromosome.
  • DNMT - DNA methyltransferase.
  • DNA - DeoxyriboNucleic Acid. The genetic material found in mammalian chromosomes and mitochondria. Consisting of 4 nucleic acids (ATCG) that combine in a triptych (3 nucleotide codon) code for protein amino acids (3nt=1aa).
  • DNA duplex - double stranded base-paired DNA forming a helix.
  • dominant inheritance - With autosomal dominant inheritance, there is an error in one of the 22 chromosome pairs. But the damaged gene dominates over the normal gene received from the other parent. If one of the parents has a disease caused by an autosomal dominant gene, all the children will have a 50 per cent risk of inheriting the dominant gene and a 50 per cent chance of not inheriting it. The children who do not inherit the damaged dominant gene will not themselves suffer from the disease, nor will they be able to pass the gene on to future children. This type of inheritance is present for example in Huntington's disease.
  • enhancer - A cis-regulatory sequence that can regulate levels of transcription from an adjacent promoter. Many tissue-specific enhancers can determine spatial patterns of gene expression in higher eukaryotes. Enhancers can act on promoters over many tens of kilobases of DNA and can be 5' or 3' to the promoter they regulate.
  • exon - a block of protein encoding sequence of DNA in a gene. Many proteins are made of several exons "stitched" or spliced together by editing out non-coding (intron) sequences.
  • fasta - a format for listing DNA sequence, where the first line has descritive information followed on the next line by the sequence without numbering.
  • GC repeat - a string of GC sequence repeated several times. Also associated with GC expansion, a mutational process that may lead eventually to serious gene expression effects.
  • gene - a sequence of DNA that encodes an individual protein.
  • genetic code - the 3 nucleotide sequence that forms a codon for a single amino acid or stop. See the gene code.
  • genome - the complete genetic information in the form of DNA available to a specific species.
  • hairpin loop - a folding of RNA generated by base pairing making a "===()" structure, the end loop and or stem of this structure can then interact with proteins or other RNA.
  • HyperD - hypermethylated domain
  • HypoD - hypomethylated domain
  • igDMR - imprinted germline differentially methylated regions
  • intron - a block of DNA within a gene not encoding a protein. Edited, spliced, out during transcription into mRNA. Originally thought not to contain any information, but more and more this appears not to be the case. Some intron sequences have been shown to regulate gene expression during development (eg c elegans, Lin 14)
  • karyotype - [Greek, karyon = kernel or nucleus + typos= stamp] The chromosomal makeup of a cell.
  • mRNA - messenger, transcribed from DNA in the nucleus and in mitochondria. Is translated by the ribosome in the cytoplasm (or mitochondrial matrix). Intermediate step in gene expression. (DNA-> mRNA-> protein).
  • mutation - any process which results in the alteration of the DNA sequence. Some conservative mutations may have no effect on the final amino acid encoded.
  • ncRNA - non-coding RNA.
  • ploidy - refers to the chromosomal genetic content of cells.
  • promoter - A regulatory region a short distance upstream from the 5' end of a transcription start site that acts as the binding site for RNA polymerase II. A region of DNA to which RNA polymerase IIbinds in order to initiate transcription.
  • point mutation - a change in a single nucleotide.
  • recessive inheritance - With autosomal recessive inheritance, the diseased individual has inherited the same gene damage from both father and mother. The damage is found on both chromosomes in the pair. But as this is not ´dominant gene damageª, neither father nor mother show any sign of disease, they are healthy carriers of the gene. We are all carriers of about five recessive genes of this type, but as spouses are seldom carriers of exactly the same damaged gene(s), all will probably go well in the next generation.
  • regulatory sequence - (regulatory region, regulatory area) is a segment of DNA where regulatory proteins such as transcription factors bind preferentially.
  • ribosome - complex of rRNA and ribosomal proteins, bind mRNA and translate it into protein.
  • RNA - RiboNucleic Acid. The intermediate nucleic acid involved in gene expression. It comes in 3 forms: tRNA, mRNA, rRNA.
  • rRNA - ribosomal, translates mRNA into protein. rRNA provides the "scaffolding" on which many ribosomal proteins are assembled as 2 subunits that themselves assemble to form a ribosome. rRNA genes are localized to the nucleolus in the nucleus, a sometimes visible region of DNA usually constantly being transcribed.
  • telomere - regions at the end of chromosomes. Shortening of the telomeres is thought to be associated with cellular aging. The enzyme that maintains the telomere is called telomerase. Introducing this gene into a cell can extend the cells lifespan.
  • transcription factor - a protein which binds to DNA activating (usually) gene expression. There are many different ways and forms that this activation can take place, but most transcription factors fall into specific classes (eg zinc fingers, helix loop helix).
  • tRNA - transfer, binds single amino acids acts as a "donor' for protein synthesis.
Other Terms Lists  
Terms Lists: ART | Birth | Bone | Cardiovascular | Cell Division | Gastrointestinal | Genetic | Hearing | Heart | Immune | Integumentary | Neural | Oocyte | Palate | Placenta | Renal | Spermatozoa | Ultrasound | Vision | Historic | Glossary


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.

  • 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

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Cite this page: Hill, M.A. 2017 Embryology Molecular Development. Retrieved May 25, 2017, from https://embryology.med.unsw.edu.au/embryology/index.php/Molecular_Development

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© Dr Mark Hill 2017, UNSW Embryology ISBN: 978 0 7334 2609 4 - UNSW CRICOS Provider Code No. 00098G