Sandbox Reserved 1120: Difference between revisions

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During the next decades, a few theories were in competition. In 1921, Calvin Bridges's works on ''Drosophila melanogaster'' seemed to reveal that male characters acquisition is due to a genic balance between the genes contained in the X chromosome and those contained in the autosomes<ref>PMID: 17769897</ref>.
During the next decades, a few theories were in competition. In 1921, Calvin Bridges's works on ''Drosophila melanogaster'' seemed to reveal that male characters acquisition is due to a genic balance between the genes contained in the X chromosome and those contained in the autosomes<ref>PMID: 17769897</ref>.
In 1930, Ronald Fisher introduced the first Y-based control of sex theory by proposing two different models : either all the genes responsible for the male characters are located on the Y chromosome or there is a Y-located gene which regulates the expression of genes elsewhere in the genome<ref>PMID: 3046910</ref>.
In 1930, Ronald Fisher introduced the first Y-based control of sex theory by proposing two different models : either all the genes responsible for the male characters are located on the Y chromosome or there is a Y-located gene which regulates the expression of genes elsewhere in the genome<ref>PMID: 3046910</ref>.
As Alfred Jost had shown the testosterone produced by the testis is responsible for the entire male phenotype acquisition<ref>PMID: 4805859</ref>, Peter Neville Goodfellow proposed in 1988, that there is a gene (''TDF'' in human, ''Tdy'' in mice)  on the Y chromosome which drives the development of the testis.<ref>PMID: 3046910</ref> In 1990, Goodfellow's hypothesis was validated with the discovery of ''Tdy'''s localisation. This gene's product (expressed during the male gonadal development) owns an amino-acid motif showing homology to other known or putative DNA-binding domains. ''Tdy'' is therefore a transcriptional factor<ref>PMID: 2374589</ref>. The same year, the human ''SRY'' gene (accepted later as the ''TDF'') was discovered<ref>PMID: 1695712</ref>.  
As Alfred Jost had shown the testosterone produced by the testis is responsible for the entire male phenotype acquisition<ref>PMID: 4805859</ref>, Peter Neville Goodfellow proposed in 1988, that there is a gene (''TDF'' in human, ''Tdy'' in mice)  on the Y chromosome which drives the development of the testis<ref>PMID: 3046910</ref>. In 1990, Goodfellow's hypothesis was validated with the discovery of ''Tdy'''s localisation. This gene's product (expressed during the male gonadal development) owns an amino-acid motif which shows homology to other known or putative DNA-binding domains. ''Tdy'' is therefore a transcriptional factor<ref>PMID: 2374589</ref>. The same year, the human ''SRY'' gene (accepted later as the ''TDF'') was discovered<ref>PMID: 1695712</ref>.  
Three dimensional structure of the SRY protein was determined in 1995 using NMR spectroscopy<ref>PMID: 7774012</ref>
Three dimensional structure of the SRY protein was determined in 1995 using NMR spectroscopy<ref>PMID:7774012</ref>.


==SRY gene==
==SRY gene==


===Generality===
The SRY gene encodes the SRY protein. The SRY protein is a transcriptional factor that induces the male phenotype in the embryo. The SRY gene is located on the [https://en.wikipedia.org/wiki/Y_chromosome Y chromosome] in the short arm (p) 11.3 <ref>[http://www.ncbi.nlm.nih.gov/gene/6736]</ref>. This gene has only one exon that contains the HMG domain (DNA-binding High-Mobility Group box domain). It means that SRY mRNA does not have an alternative splicing, so there is only one isoforme of SRY protein<ref> McElreavey K, Barbaux S, Ion A, Fellous M. The genetic basis of murine and human sex determination: a review. Heredity. 1995 Dec;75 ( Pt 6):599–611. [http://www.ncbi.nlm.nih.gov/pubmed/8575930]</ref>. Moreover, the human genome contains only one copy of the SRY gene, whereas the mouse genome contains 6 copy of this gene<ref> Sekido R, Lovell-Badge R. Genetic control of testis development. Sex Dev Genet Mol Biol Evol Endocrinol Embryol Pathol Sex Determ Differ. 2013;7(1-3):21–32 </ref>.
 
The SRY gene encodes the SRY protein. The SRY protein is a transcriptional factor inducing the male phenotype in embryo. The SRY gene is located on the [https://en.wikipedia.org/wiki/Y_chromosome Y chromosom] in the short arm (p) 11.3 <ref>[http://www.ncbi.nlm.nih.gov/gene/6736]</ref>. This gene has only one exon containing the HMG domain (DNA-binding high-mobility group box domain). That's means that SRY mRNA does not have a alternative splicing, so there is one isoform of SRY protein.<ref> McElreavey K, Barbaux S, Ion A, Fellous M. The genetic basis of murine and human sex determination: a review. Heredity. 1995 Dec;75 ( Pt 6):599–611. [http://www.ncbi.nlm.nih.gov/pubmed/8575930]</ref>. Moreover,the human genome contains one copy of the SRY gene, whereas the mouse genome contains 6 copy of this gene. <ref> Sekido R, Lovell-Badge R. Genetic control of testis development. Sex Dev Genet Mol Biol Evol Endocrinol Embryol Pathol Sex Determ Differ. 2013;7(1-3):21–32 </ref>


===Sequence of the SRY gene===
===Sequence of the SRY gene===
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===Regulation of the expression of the SRY gene===
===Regulation of the expression of the SRY gene===


In humans, the SRY promoter is found at −408 bp to −95 bp upstream of the ATG initiation codon. Moreover, the SRY gene has enhancers at -727 pb upstream of the ATG initiation codon. The linkage between regulatory proteins and this enhancers have the property to increase the production of SRY protein. These regulatory proteins could be: SF1 (steroidogenic factor 1), SP1  and WT 1 (Wilms tumor). <ref>Harley VR, Clarkson MJ, Argentaro A. The Molecular Action and Regulation of the Testis-Determining Factors, SRY (Sex-Determining Region on the Y Chromosome) and SOX9 [SRY-Related High-Mobility Group (HMG) Box 9]. Endocr Rev. 2003 Aug 1;24(4):466–87. [http://press.endocrine.org/doi/10.1210/er.2002-0025?url_ver=Z39.88-2003&rfr_id=ori%3Arid%3Acrossref.org&rfr_dat=cr_pub%3Dpubmed&]</ref>
In humans, the SRY promoter is located between −408 and −95 bp. Moreover, the SRY gene has enhancers at -727 pb. The linkage between regulatory proteins and these enhancers has the property to increase the production of SRY proteins. These regulatory proteins could be: SF1 (steroidogenic factor 1), SP1  and WT 1 (Wilms tumor). <ref>Harley VR, Clarkson MJ, Argentaro A. The Molecular Action and Regulation of the Testis-Determining Factors, SRY (Sex-Determining Region on the Y Chromosome) and SOX9 [SRY-Related High-Mobility Group (HMG) Box 9]. Endocr Rev. 2003 Aug 1;24(4):466–87. [http://press.endocrine.org/doi/10.1210/er.2002-0025?url_ver=Z39.88-2003&rfr_id=ori%3Arid%3Acrossref.org&rfr_dat=cr_pub%3Dpubmed&]</ref>.


*SF1: this transcriptional factor belong to the family of nuclear hormone receptor and contains a zinc finger. The activation of this protein requires a ligand (hormone).
*'''SF1''': this transcriptional factor belongs to the family of nuclear hormone receptors and contains a zinc finger. The activation of this protein requires a ligand (hormone).


*SP1: this transciprional factor is a ubiquitous protein binding in site containing rich-GC sequences and implicated in the transcription of many genes. Moreover, this protein contains a zinc finger.
*'''SP1''': this transcriptional factor is an ubiquitous protein which binds rich GC-sites and is implicated in the transcription of many genes. Moreover, this protein contains a zinc finger.


*WT1:this transcriptional factor transactives SRY gene, it contains a zinc finger. <ref>Larney C, Bailey TL, Koopman P. Switching on sex: transcriptional regulation of the testis-determining gene Sry. Dev Camb Engl. 2014 Jun;141(11):2195–205. </ref>  
*'''WT1''' :this transcriptional factor transactivates the SRY gene. It contains a zinc finger. <ref>Larney C, Bailey TL, Koopman P. Switching on sex: transcriptional regulation of the testis-determining gene Sry. Dev Camb Engl. 2014 Jun;141(11):2195–205</ref>.


==Structure==
==Structure==


===The SRY-HMG domain (HMG-Box)===
===The SRY-HMG domain (HMG-Box)===
'''SRY-HMG''' stands for '''S'''ex determining '''R'''egion '''Y''' - '''H'''igh '''M'''obility '''G'''roup domain.
'''SRY-HMG''' stands for '''S'''ex determining '''R'''egion '''Y''' - '''H'''igh '''M'''obility '''G'''roup domain.
It is approximately 80 residues long. It mediates the binding of the protein to the minor groove of DNA. It is the most important part of the SRY protein. Not only because it enable the protein to bind the DNA but because even a little mutation can cause an inactivation of the protein.
It is approximately 80 residues-long. It mediates the binding of the protein to the minor groove of DNA. It is the most important part of the SRY protein. Not only because it enables the protein to bind the DNA but also because even a single mutation can cause an inactivation of the protein.


It has a Twisted L shape meaning that it has a long (28Å) and a short (22Å) arm. The HMG Box is made of 3 helices, its N-term and C-term are irregular. The overall structure is stabilized by a hydrophobic core especially at the intersection of the 3 helices where 3 aromatics cycles meet, surrounnded by aliphatic aminoacids.
It has a twisted L shape: it has a long (28Å) and a short (22Å) arm. The HMG Box is made of 3 helices. Its N-term and C-term domains are irregular. The overall structure is stabilized by a hydrophobic core especially at the intersection of the 3 helices where 3 aromatics cycles meet, surrounded by aliphatic aminoacids.
See the different structure:
See the different structures:
*<scene name='71/719861/Helix_1/3'>Helix 1</scene>
*<scene name='71/719861/Helix_1/3'>Helix 1</scene>
*<scene name='71/719861/Helix_2/2'>Helix 2</scene>
*<scene name='71/719861/Helix_2/2'>Helix 2</scene>
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