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Sex-reversing mutations in the CaM-NLS reduce SRY nuclear accumulation (A) The SRY protein is shown diagrammatically, with the CaM-NLS and β-NLSs flanking the HMG-box (single-letter amino acid code) highlighted together with the sex-reversing point mutations analysed in the present study (see the Materials and methods section for patient details). (B) TM4 cells were transiently transfected to express the indicated GFP-SRY-HMG/FL fusion proteins, and imaged live 24 h later by CLSM using a 40× water-immersion objective. (C) Results of quantitative analysis, whereby CLSM images such as those in (B) were analysed using ImageJ software for the extent of nuclear accumulation measured as the Fn/c (see the Materials and methods section). Results are means + − S.E.M. (n >7); ***P < 0.0001; **P < 0.005; *P < 0.01 for Fn/c values for the NLS mutant constructs significantly different from those of WT.
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The HMG (high-mobility group)-box-containing chromatin-remodelling factor SRY (sex-determining region on the Y chromosome) plays a key role in sex determination. Its role in the nucleus is critically dependent on two NLSs (nuclear localization signals) that flank its HMG domain: the C-terminally located 'beta-NLS' that mediates nuclear transport th...
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... other HMG proteins, SRY is able to bind and bend specific DNA targets through its HMG-box domain [3,8]. The majority of sex-reversing mutations in SRY result in impaired DNA binding/bending, but a number, several of which do not affect DNA binding, map to one of SRY's two independently functioning NLSs (nuclear localization signals) that flank the HMG-box domain ( Figure 1) [3,4,7,[9][10][11]. Little is known regarding the mechanism by which the N-terminal 'CaM-NLS' (amino acids 59-77) functions, apart from the fact that it can bind the Ca 2+ -binding protein CaM (calmodulin) in vitro [12], whereas the C-terminal 'β-NLS' (amino acids 128-134) appears to be conventional, mediating nuclear import dependent on the Impβ1 (importin β1) member of the Imp superfamily and the guanine- nucleotide-binding protein Ran [13]. ...
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... (N) and cytoplasmic (C) density was determined and used to derive the nuclear to cytoplasmic ratio (N/C) to assess the presence of GFP-SRY in the nucleus compared with cytoplasm. Immunoblot analysis of whole cell lysates indicated that all constructs were expressed to comparable levels and in intact form (see Supplementary Figure S1 at http://BiochemJ.org/bj/430/bj4300039add.htm). ...
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... Table 1), of particular interest being those that do not have any impact on any known activities of SRY, including DNA binding and bending [10]. To test whether these affect SRY's nuclear import capabilities directly, plasmids encoding GFP-SRY fusion proteins (both SRY-FL and SRY-HMG) with or without the M64T, F67V, R76P, Y127C and R133W point mutations ( Figure 1A) were transiently expressed in the testicular TM4 Sertoli cell line, and cells were subjected to CLSM imaging ( Figure 1B). Exclusively nuclear localization was observed for the WT SRY protein, with clear cytoplasmic localization in addition to nuclear accumulation observed for all of the NLS mutant derivatives ( Figure 1B). ...
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... Table 1), of particular interest being those that do not have any impact on any known activities of SRY, including DNA binding and bending [10]. To test whether these affect SRY's nuclear import capabilities directly, plasmids encoding GFP-SRY fusion proteins (both SRY-FL and SRY-HMG) with or without the M64T, F67V, R76P, Y127C and R133W point mutations ( Figure 1A) were transiently expressed in the testicular TM4 Sertoli cell line, and cells were subjected to CLSM imaging ( Figure 1B). Exclusively nuclear localization was observed for the WT SRY protein, with clear cytoplasmic localization in addition to nuclear accumulation observed for all of the NLS mutant derivatives ( Figure 1B). ...
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... test whether these affect SRY's nuclear import capabilities directly, plasmids encoding GFP-SRY fusion proteins (both SRY-FL and SRY-HMG) with or without the M64T, F67V, R76P, Y127C and R133W point mutations ( Figure 1A) were transiently expressed in the testicular TM4 Sertoli cell line, and cells were subjected to CLSM imaging ( Figure 1B). Exclusively nuclear localization was observed for the WT SRY protein, with clear cytoplasmic localization in addition to nuclear accumulation observed for all of the NLS mutant derivatives ( Figure 1B). This result was confirmed by quantifying the extent of nuclear accumulation through image analysis (see Figure 1C), whereby the nuclear to cytoplasmic ratio (Fn/c) was determined as described previously [29,30]. ...
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... nuclear localization was observed for the WT SRY protein, with clear cytoplasmic localization in addition to nuclear accumulation observed for all of the NLS mutant derivatives ( Figure 1B). This result was confirmed by quantifying the extent of nuclear accumulation through image analysis (see Figure 1C), whereby the nuclear to cytoplasmic ratio (Fn/c) was determined as described previously [29,30]. The extent of nuclear accumulation of SRY appeared to be similar for full-length and HMG-derivative constructs, with the WT constructs showing Fn/c values of ∼ 60 (indicative of 60-fold higher levels in the nucleus than in the cytoplasm). ...
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... extent of nuclear accumulation of SRY appeared to be similar for full-length and HMG-derivative constructs, with the WT constructs showing Fn/c values of ∼ 60 (indicative of 60-fold higher levels in the nucleus than in the cytoplasm). In comparison, constructs containing the β-NLS and CaM-NLS mutations showed significantly (P < 0.01) reduced (∼ 40 -80 %) levels of nuclear accumulation (Fn/c <30; see Figure 1C). Essentially identical results were observed for the constructs expressed in the GC-2 testicular (see Figures 4C and 4D and Table 1) and P19 embryonic carcinoma (results not shown) cell lines, as well as the COS-7 cell line from kidney (see below), suggesting that the mechanisms determining nuclear import of SRY are not specific to testicular cells. ...
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... results were observed for analysis of GFP-SRY-FL proteins ( Figure 2B), with significantly (P < 0.007) higher levels of WT GFP-SRY-FL protein in the nuclear fraction compared with the cytoplasmic fraction, compared with the M64T, R76P and R133W (93, 29 and 71 % reduced N/Cs respectively compared with WT) NLS mutant derivatives. These results clearly support the idea that sex-reversing mutations in both the CaM-and β-NLS impair SRY nuclear accumulation in living cells, completely consistent with the results generated by CLSM analysis (Figure 1); the results strongly imply that CaM plays an important role in SRY nuclear import. ...
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... images of cells after 18-20 min of incubation are shown on the left in each case, with images for nuclear exclusion of TR70 to demonstrate nuclear integrity on the right. (C) Quantitative analysis is shown for nuclear uptake over time, whereby CLSM images such as those on the left were analysed as described in Figure 1(C). Results are means + − S.E.M. for a single typical experiment, from a series of three similar experiments (see Table 2 for pooled data), with each data point representing more than three separate measurements of Fn and Fc above background. ...
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... with the results for native PAGE, the CaM-NLS mutants all bound to Impβ1 with high affinity comparable with WT, in contrast with the Y127C mutant, which showed ∼ 4-fold higher K d and significantly (P < 0.0001) impaired Impβ1 binding (Table 3 and Figure 5B, bottom panels). Both native PAGE and AlphaScreen ® assay results clearly imply that the CaM-NLS mutations directly affect CaM, but not Impβ1 binding; this presumably represents the basis of the reduced nuclear localization (Figures 1, 2 and 4) and lack of CDZ sensitivity of nuclear accumulation (Figure 3) of SRY carrying CaM-NLS mutations compared with WT. ...
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... The Met64Thr mutation in the SRY gene can potentially impact the protein's structure and function, thereby leading to impaired transcriptional regulation of target genes involved in male sexual development (Harley et al., 2003;Kaur et al., 2010). Based on the findings, the Met64Thr variant in the HMG domain of SRY exhibits altered DNA binding and reduced PRM1 promoter activity compared with the wild-type SRY. ...
The male sex-determining gene, sex-determining region on the Y chromosome (SRY), is expressed in adult testicular germ cells; however, its role in regulating spermatogenesis remains unclear. The role of SRY in the postmeiotic gene expression was investigated by determining the effect of SRY on the promoter of the haploid-specific Protamine 1 (PRM1) gene, which harbors five distinct SRY-binding motifs. In a luciferase reporter assay system, SRY upregulates PRM1 promoter activity in vitro in a dose-dependent manner. Through a gel-shift assay involving a 31-bp DNA fragment encompassing the SRY element within the PRM1 promoter, the third SRY-binding site on the sense strand (-373/-367) was identified as crucial for PRM1 promoter activation. This assay was extended to analyze 9 SRY variants found in the testicular DNA of 44 azoospermia patients. The findings suggest that SRY regulates PRM1 promoter activity by directly binding to its specific motif within the PRM1 promoter.
... Sox proteins contain transactivation domains and nuclear localization signals. For nuclear transport, Sox proteins have binding domains for CaM and importins [13,14]. In addition, the murine Catsper1 promoter has elements for functional interaction with Sox, Creb, Crem, and ER transcription factors [15]. ...
... Calmidazolium (CMZ) (1-[bis(p-chlorophenyl) methyl]-3-[2,4-dichloro-3-(2,4-dichlorobenzyloxy) phenethyl] imidazolinium chloride), is a potent CaM inhibitor. Interestingly, it has been suggested that CMZ may affect the nuclear transport of Sox proteins containing the CaM-binding domain (Sox9 and Sry) in male germ cells [13,14]. Inhibition of Sox nuclear transport could affect the expression of genes during spermatogenesis and eventually affect the fertility of the male gametes. ...
... The inhibition of calmodulin by CMZ prevents the nuclear transport of Sox 9 and SRY, proteins that contain calmodulin-binding domains [13,14]. CMZ might alter the expression of diverse genes under Sox control during spermatogenesis and affect the fertility of male germ cells. ...
The CatSper channel localizes exclusively in the flagella of sperm cells. The Catsper1 protein, together with three pore units, is essential for the CatSper Channel formation, which produces flagellum hyperactivation and confers sperm fertility. Catsper1 expression is dependent on Sox transcription factors, which can recognize in vitro at least three Sox binding sites on the promoter. Sox transcription factors have calmodulin-binding domains for nuclear importation. Calmodulin (CaM) is affected by the specific inhibitor calmidazolium (CMZ), which prevents the nuclear transport of Sox factors. In this work, we assess the regulation of the Catsper1 promoter in vivo by Sox factors in the murine testis and evaluate the effects of the inhibitor calmidazolium on the expression of the Casper genes, and the motility and fertility of the sperm. Catsper1 promoter has significant transcriptional activity in vivo; on the contrary, three Sox site mutants in the Catsper1 promoter reduced transcriptional activity in the testis. CaM inhibition affects Sox factor nuclear transport and has notable implications in the expression and production of Catsper1, as well as in the motility and fertility capability of sperm. The molecular mechanism described here might conform to the basis of a male contraceptive strategy acting at the transcriptional level by affecting the production of the CatSper channel, a fundamental piece of male fertility.
... The SRY protein structure has conserved DNA binding sites between 58 and 137 amino acid sequences. These 80 amino acid residues share high extent of homology with DNA binding, bending and nuclear localising signals (NLS) motiff known as the high-mobility-group (HMG box), which contains within it strongly conserved evolutionary nucleotide sequences (Harley at el., 2003;Kaur et al., 2010). ...
... Ultimately loss of Arginine positively charged amino acid residue prevent formation of SRY-DNA hydrogen bonds, there by decreasing the DNA binding activity of SRY protein (Harley, Clarkson, et al., 2003;Harley, Layfield, et al., 2003;Kaur et al., 2010). The alteration of polar positively charged Arginine amino acid at position 62, 75 and 76 is the impairment of interaction between transcription factor SRY protein and disturbed DNA binding, bending and nuclear localising signal affinity (Hanover et al., 2009;Sim et al., 2005). ...
... The DNA binding HMG domain of SRY protein contains the n-NLS region (amino acids 59-77) and consists of two highly basic regions separated by 11 residues, resembling the bipartite NLS identified in nucleoplasmin (Kaur et al., 2010;Sim et al., 2011). It has been found that missense mutation in their nNLS, R62G, M64T, F67V, R75N and R76P causes defect in the Calmodulin (CaM) mediated binding/SRY nuclear import pathway, which results in 46,XY sex reversal female or pure gonadal dysgenesis (Swyer syndrome) (Fan et al., 2016;Harley, Layfield, et al., 2003;Sim et al., 2005). ...
The SRY initiates cascade of gene expression that transforms the undifferentiated gonad, genital ridge into testis. Mutations of the SRY gene is associated with complete gonadal dysgenesis in females with 46,XY karyotype. Primary amenorrhea is one of the clinical findings to express the genetic cause in 46,XY sex reversal. Here, we report a 26-year-old married woman presenting with primary amenorhea and complete gonadal dysgenesis. The clinical phenotypes were hypoplastic uterus with streak gonad and underdeveloped secondary sexual characters. The cytogenetic analysis confirmed 46,XY sex reversal karyotype of a female. Using molecular approach, we screened open reading frame of the SRY gene by PCR and targeted DNA Sanger sequencing. The patient was confirmed with nucleotide substitution (c.226C>A; p.Arg76Ser) at in HMG box domain of SRY gene that causes 46,XY sex reversal female. Mutation prediction algorithms suggest that alteration might be disease causing mutation and mutated (p.Arg76Ser) amino acid deleteriously affects HMG box nNLS region of SRY protein. Clinical phenotypes and in silico analysis confirmed that missense substitution (p.Arg76Ser) impaired nNLS binding Calmodulin-mediated nuclear transport of SRY from cytoplasm to nucleus. The mutation affects down regulation of male sex differentiation pathway and is responsible for 46,XY sex reversal female with gonadal dysgenesis.
... These roles require precise and timely localization of SOX2 to the nucleus. To gain access to the nucleus, SOX proteins harbor two NLSs, located distally at the N-and C-terminus of the DNA-binding domain [7][8][9][10][11][12][13][14][15] . This arrangement is conserved across all SOX family members ( Fig. 1), and mutations within these regions can impair nuclear localization, cause severe developmental disease, and are associated with poor prognosis in cancer 9,16-19 (see also "Abstract" section). ...
... SOX2 bound IMPα3 through an extensive and contiguous interface across ARM domains 1-9 of IMPα3 (Fig. 2). The N-terminal NLS (NLS1) was previously reported to be bipartite 7,15,28 , and therefore expected to be bound at both the major and minor sites on IMPα3. However, we found instead that, SOX2 residues Arg40, Lys42, and Arg43 were bound at the minor site (IMPα3 ARM domains 6-8; Fig. 2) and that SOX2 Arg57 was bound at ARM 9, outside of the minor site. ...
SOX (SRY-related HMG-box) transcription factors perform critical functions in development and cell differentiation. These roles depend on precise nuclear trafficking, with mutations in the nuclear targeting regions causing developmental diseases and a range of cancers. SOX protein nuclear localization is proposed to be mediated by two nuclear localization signals (NLSs) positioned within the extremities of the DNA-binding HMG-box domain and, although mutations within either cause disease, the mechanistic basis has remained unclear. Unexpectedly, we find here that these two distantly positioned NLSs of SOX2 contribute to a contiguous interface spanning 9 of the 10 ARM domains on the nuclear import adapter IMPα3. We identify key binding determinants and show this interface is critical for neural stem cell maintenance and for Drosophila development. Moreover, we identify a structural basis for the preference of SOX2 binding to IMPα3. In addition to defining the structural basis for SOX protein localization, these results provide a platform for understanding how mutations and post-translational modifications within these regions may modulate nuclear localization and result in clinical disease, and also how other proteins containing multiple NLSs may bind IMPα through an extended recognition interface.
... The N-terminal NLS is a calmodulin binding region (Hanover et al., 2009), which mediates the calcium/calmodulin pathway. It has been manifested that the nuclear accumulation of SOX9 protein is dependent on CaM, directly mediating the entry of SOX9 protein into the nucleus by binding to the N-terminal NLS (Argentaro et al., 2003;Kaur et al., 2010), which is in accord with the results that calcium signaling pathway exists in renal development (MD49 vs MH; MD31 vs MD36); The C-terminal NLS Wang et al. Gene xxx (xxxx) xxx-xxx is closely involved in the importin-β pathway, NLS interacts with the importin-β to form a complex that binds to the nucleoprotein RanBP2 in order to mediate nuclear translocation through the nucleopore (Malki et al., 2010). ...
SOX9 plays a crucial, extensive and conservative role in the process of somatic tissue development and adult regeneration through the positive self-regulation mediated by SOM across all vertebrates. In this study, we have cloned SOX9 from the kidney of hatchling Alligator sinensis. The full-length of SOX9 cDNA is 3878 bp with an open reading frame encoding 494 amino acids. Amino acid alignment analyses indicated that the SOX9 exhibit highly conserved functional domains. Using the droplet digital PCR, the mRNA abundances of SOX9 during nephrogenesis in A. sinensis showed prominent changes in the embryonic development, suggesting that SOX9 might combines a vital role in the regulation of complex renal development. Interestingly, we detected the nucleocytoplasmic shuttling of SOX9 protein using immunofluorescence, implying that nucleocytoplasmic shuttling is critical to the regulation of SOX9 in the renal embryonic development. Collectively, these data provide an important foundation for further studies on renal developmental biology and molecular biology of non-mammalian SOX9. Furthermore, it provides new insights into the phenomenon of SOX9 nucleocytoplasmic shuttling in Alligator sinensis, which is probably of great significance to the development of kidney metanephros embryo.
... For SRY, the calmodulin-dependent import plays a major role during high intracellular calcium conditions. In contrast, the importin-β1-dependent import is facilitated under low calcium concentrations [6,13,14,28]. Applying this model to NCAM, its import into the nucleus would be guaranteed during different cell conditions highlighting the importance of nuclear presence of NCAM. Such a mechanism remains to be identified for other transmembrane proteins. ...
The neural cell adhesion molecule (NCAM) is important for neural development and for plasticity in adult brain. Previous studies demonstrated a calmodulin-dependent import of a transmembrane fragment of NCAM into the nucleus that regulates gene expression. In a protein macroarray we identified importin-β1 as a potential interaction partner of NCAM's cytoplasmic tail. The interaction was verified and an importin-β1-dependent import of NCAM into the nucleus could be demonstrated using quantitative immunofluorescence analysis. Generation of NCAM deletion mutants revealed that the last amino acids of the cytoplasmic region of NCAM are dispensable whereas other parts of NCAM's cytoplasmic tail take part in its nuclear translocation. With this study we propose an alternative nuclear route for NCAM via the classical importin-mediated import.
... SRY is a sex-determination gene on the Y chromosome of mammals that is responsible for the initiating male sex determination [8]. Mutations in the high-mobility-group (HMG) box, a conserved DNA-binding domain of SRY, induces hermaphroditism syndrome in XY individuals [12]. ...
Hermaphroditism is a rare disorder that affects sexual development, resulting in individuals with both male and female sexual organs. Hermaphroditism is caused by anomalies in genes regulating sex determination, gonad development, or expression of hormones and their receptors during embryonic development during sexual differentiation. SRY is a sex-determination gene on the Y chromosome that is responsible for initiating male sex determination in mammals. In this study, we introduced CRISPR/Cas9-mediated mutations in the HMG region of the rabbit SRY As expected, SRY -mutant chimeric rabbits were diagnosed with hermaphroditism, characterized by possessing ovotestis, testis, ovary and uterus simultaneously. Histopathology analysis revealed that the testicular tissue was immature and lacked spermatogenic cells, while the ovarian portion appeared normal and displayed follicles at different stages. This is the first report of a rabbit hermaphroditism model generated by the CRISPR/Cas9 system. This novel rabbit model could advance our understanding of the pathogenesis of hermaphroditism, and identify novel therapies for human clinical treatment of hermaphroditism.
... In mammals, the sex-determining gene, SRY, which is expressed specifically in the genital ridges, facilitates gender determination [1,2]. Mutation or dysfunction of the HMG box, a conserved DNA-binding domain of the SRY protein, have been shown to induce male-tofemale sex reversal syndrome in XY individuals [3,4]. In addition, mutations in the 5' regulatory region of the SRY gene were also responsible for sex reversal in clinical studies [5]. ...
Sex-determining region Y is a crucial gene that initiates male sex determination in mammals. Mutations of the Sp1-binding site in the 5' flanking region of SRY are associated with clinical male-to-female sex reversal syndrome, although such occurrences are rare and, until now, have not been reported in animal models. In this study, we mutated Sp1-binding sites in the 5' flanking region of the rabbit SRY gene using the CRISPR/Cas9 system. As expected, the SRY-Sp1 knockout rabbits had female external and internal genitalia and exhibited normal female copulatory behaviors, but they were infertile, and the adults displayed reduced follicles. Interestingly, we successfully obtained offspring from sex-reversed SRY-Sp1 knockout rabbits using embryo transfer. In summary, our study demonstrates that Sp1 is a major regulator in SRY gene transcription, and mutations of the Sp1 binding sites (Sp1-B and Sp1-C) in the 5' flanking region of SRY induce sex reversal in rabbits, which can be used as targets for clinical research of male-to-female sex reversal syndrome. Additionally, we provide the first evidence that sex reversal syndrome patients have the potential to become pregnant with the use of embryo transfer.
... The SRY protein contains a single homeobox domain called high mobility group (HMG), which is the most important part in SRY, and majority of the reported mutations occur within it. SRY plays a role as transcription factor [6]. It is assumed that SRY works as a DNA binding factor affecting local chromatin structure approximate to its target genes to boost transcription initiation [7,8]. ...
... The mutation 224G>T (R75M) locates at N-terminal of the HMG box, where exists a functional NLS [13,14,15,16,17,6,18]. Our experiment showed the mutant protein was severely inhibited for nuclear import and greatly accumulated in cytoplasm. ...
SRY-mutation-caused sex reversal is a rare disease and mostly associated with a de novo mutation since the patients with defective SRY is infertile. There are many reports about SRY-mutation associated 46, XY ovarian disorder of sex development (DSD), but few described their molecular mechanism. Here we report a de novo mutation 224G>T (R75M) in SRY associated with a phenotypic female, 46, XY karyotype and dysgerminoma. The wild and mutated SRY were cloned into recombinant plasmid and expressed in cells in vitro, the result showed the mutated SRY is greatly accumulated in cytoplasm while the wild type SRY is mostly localized in nucleus. To make sure no other genes were involved, we performed the trio-based whole exome sequencing using the DNA samples from the proband and the parents, and no mutations were identified especially in DHH, NR0B1, NR5A1, SOX9 and MAP3K1, indicating the de novo mutation in SRY is the single defect responsible for the female sex reversal. We also used bioinformatics simulation analysis to predict impact of the mutation on SRY function, and find the R75 in wild type SRY can form a hydrogen bond with serine at 91 (S91) that make the SRY protein well fit into the minor groove of target DNA, while the M75 in the mutated SRY can’t. Finally, we reviewed SRY mutations based on the available references and analyzed the mutation distribution patterns according to density and continuity, which may be useful for further study of the SRY structure, function, and its relatedness with DSD.
... This facilitates transport through the nuclear pore complex(NPC) found embedded in nuclear envelope and release the nucleus on interaction with G protein monomeric binding proteins Ran activated G protein bound form [13,14]. The 2 nd N terminal NLS, Calmodulin (CaM)-NLSbinds the Ca 2+ binding protein CaM [15] Kaur, et al., showed a dual nuclear import and calmodulin dependent nuclear import importance in role of SRY in sex reversal after examining missense mutations in SRY CaM NLS from human XY sex reversal females [16,17]. ...
SRY related high mobility group box (Sox) transcription factors have emerged in the animal kingdom to help cells maintain stemness, commit to a specific lineage, proliferate or die. Encoded by 20 genes in humans and mice they show a highly conserved high-mobility group boxdomain, which was originally identified in SRY, the sex determining region on the Y chromosome. This has derived from a high mobility group domain characterized of chromatin associated proteins. HMG (high mobility group) non histone chromosomal proteins include the AT hook, HMGN, and HMG domain families.
