Loss of the sulfate transporter Slc13a4 in placenta causes severe fetal abnormalities and death in mice

Rakoczy, Joanna; Zhang, Zhe; Bowling, Francis; Dawson, Paul A.; Simmons, David G.

doi:10.1038/cr.2015.100

Cited by 18 publications

(26 citation statements)

References 15 publications

(15 reference statements)

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“…A related sulfate transporter, SLC13A4, is expressed in the placenta where it mediates sulfate transfer to the developing fetus [10] , [12] . The physiological importance of maintaining high maternal plasma sulfate levels via SLC13A1, as well as placental sulfate transfer via SLC13A4, has been highlighted with findings of late-gestational fetal demise in Slc13a1 and Slc13a4 knockout mice [13] , [14] , [15] .…”

Section: Introductionmentioning

confidence: 99%

Structure, organization and tissue expression of the pig SLC13A1 and SLC13A4 sulfate transporter genes

Barnes

Eiby

Lee

et al. 2017

Biochemistry and Biophysics Reports

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Sulfate is an obligate nutrient for fetal growth and development. In mice, the renal Slc13a1 sulfate transporter maintains high maternal circulating levels of sulfate in pregnancy, and the placental Slc13a4 sulfate transporter mediates sulfate supply to the fetus. Both of these genes have been linked to severe embryonal defects and fetal loss in mice. However, the clinical significance of SLC13A1 and SLC13A4 in human gestation is unknown. One approach towards understanding the potential involvement of these genes in human fetal pathologies is to use an animal model, such as the pig, which mimics the developmental trajectory of the human fetus more closely than the previously studied mouse models. In this study, we determined the tissue distribution of pig SLC13A1 and SLC13A4 mRNA, and compared the gene, cDNA and protein sequences of the pig, human and mouse homologues. Pig SLC13A1 mRNA was expressed in the ileum and kidney, whereas pig SLC13A4 mRNA was expressed in the placenta, choroid plexus and eye, which is similar to the tissue distribution in human and mouse. The pig SLC13A1 gene contains 15 exons spread over 76 kb on chromosome 8, and encodes a protein of 594 amino acids that shares 90% and 85% identity with the human and mouse homologues, respectively. The pig SLC13A4 gene is located approximately 11 Mb from SLC13A1 on chromosome 8, and contains 16 exons spanning approximately 70 kb. The pig SLC13A4 protein contains 626 amino acids that share 91% and 90% identity with human and mouse homologues, respectively. The 5’-flanking region of SLC13A1 contains several putative transcription factor binding sites, including GATA-1, GATA-3, Oct1 and TATA-box consensus sequences, which are conserved in the homologous human and mouse sequences. The 5’-flanking sequence of SLC13A4 contains multiple putative transcription factor consensus sites, including GATA-1, TATA-box and Vitamin D responsive elements. This is the first report to define the tissue distribution of pig SLC13A1 and SLC13A4 mRNAs, and compare the gene, cDNA, 5’-flanking region and protein sequences to human and mouse.

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Section: Introductionmentioning

confidence: 99%

Structure, organization and tissue expression of the pig SLC13A1 and SLC13A4 sulfate transporter genes

Barnes

Eiby

Lee

et al. 2017

Biochemistry and Biophysics Reports

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“…In pregnant women, plasma sulfate levels increase by approximately 2-fold in early pregnancy (10-20 weeks gestation), with levels peaking in late gestation (30-37 weeks) at a time when fetal demands for sulfate are high (Dawson et al, 2015b). Similarly, circulating M A N U S C R I P T (Lee et al, 2006;Bowling et al, 2012).…”

Section: Reduced Reproduction and Fecundity Linked To Sulfate Maintenmentioning

confidence: 99%

“…1B). The final CDO1 and CTH gene expression in human and rodent fetal tissues (Gaull et al, 1972;Loriette and Chatagner, 1978;Rakoczy et al, 2015a), suggests that the developing fetus lacks the capacity to generate sulfate and likely explains the late gestational fetal death in Slc13a4 null-mice when placental sulfate supply from mother to fetus is blocked (Rakoczy et al, 2015b).…”

Section: Sulfate Generation Genesmentioning

confidence: 99%

“…Disruption of the SLC13A1 gene leads to renal sulfate wasting and hyposulfataemia in humans, mice, dogs and sheep (Dawson et al, 2003;Bowling et al, 2012;Neff et al, 2012;Zhao et al, 2012), whereas loss of the SLC13A4 gene blocks placental sulfate supply to the developing fetus, which causes severe developmental abnormalities and late gestational fetal death in mice (Rakoczy et al, 2015b). Interestingly, disruptions to the SLC13A1 and SLC13A4 genes do not cause any major cellular pathology in the tissues where these genes are expressed but rather lead to reduced circulating sulfate levels which in turn decreases sulfonation capacity in cells throughout the body (Dawson et al, 2003;Lee et al, 2006;Rakoczy et al, 2015b).…”

Section: Sulfate Transporter Genesmentioning

confidence: 99%

“…Interestingly, disruptions to the SLC13A1 and SLC13A4 genes do not cause any major cellular pathology in the tissues where these genes are expressed but rather lead to reduced circulating sulfate levels which in turn decreases sulfonation capacity in cells throughout the body (Dawson et al, 2003;Lee et al, 2006;Rakoczy et al, 2015b). In particular, certain cells such as chondrocytes, endothelial cells and hepatocytes, which have a high sulfate requirement, are linked to skeletal, vascular and hepatic metabolism phenotypes in animals with disrupted SLC13A1 and SLC13A4 genes (Table 5).…”

Section: Sulfate Transporter Genesmentioning

confidence: 99%

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Genetics and pathophysiology of mammalian sulfate biology

Langford

Hurrion

Dawson

2017

Journal of Genetics and Genomics

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Nutrient sulfate is essential for numerous physiological functions in mammalian growth and development. Accordingly, disruptions to any of the molecular processes that maintain the required biological ratio of sulfonated and unconjugated substrates are likely to have detrimental consequences for mammalian physiology. Molecular processes of sulfate biology can be broadly grouped into four categories: firstly, intracellular sulfate levels are maintained by intermediary metabolism and sulfate transporters that mediate the transfer of sulfate across the plasma membrane; secondly, sulfate is converted to 3'-phosphoadenosine 5'-phosphosulfate (PAPS), which is the universal sulfonate donor for all sulfonation reactions; thirdly, sulfotransferases mediate the intracellular sulfonation of endogenous and exogenous substrates; fourthly, sulfate is removed from substrates via sulfatases. From the literature, we curated 91 human genes that encode all known sulfate transporters, enzymes in pathways of sulfate generation, PAPS synthetases and transporters, sulfotransferases and sulfatases, with a focus on genes that are linked to human and animal pathophysiology. The predominant clinical features linked to these genes include neurological dysfunction, skeletal dysplasias, reduced fecundity and reproduction, and cardiovascular pathologies. Collectively, this review provides reference information for genetic investigations of perturbed mammalian sulfate biology.

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Dissecting the Impact of Maternal Androgen Exposure on Developmental Programming through Targeting the Androgen Receptor

Lu,

Jiang,

et al. 2024

Advanced Science

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Women with polycystic ovary syndrome (PCOS) exhibit sustained elevation in circulating androgens during pregnancy, an independent risk factor linked to pregnancy complications and adverse outcomes in offspring. Yet, further studies are required to understand the effects of elevated androgens on cell type‐specific placental dysfunction and fetal development. Therefore, a PCOS‐like mouse model induced by continuous androgen exposure is examined. The PCOS‐mice exhibited impaired placental and embryonic development, resulting in mid‐gestation lethality. Co‐treatment with the androgen receptor blocker, flutamide, prevents these phenotypes including germ cell specification . Comprehensive profiling of the placenta by whole‐genome bisulfite and RNA sequencing shows a reduced proportion of trophoblast precursors, possibly due to the downregulation of Cdx2 expression. Reduced expression of Gcm1, Synb, and Prl3b1 is associated with reduced syncytiotrophoblasts and sinusoidal trophoblast giant cells, impairs placental labyrinth formation. Importantly, human trophoblast organoids exposed to androgens exhibit analogous changes, showing impaired trophoblast differentiation as a key feature in PCOS‐related pregnancy complications. These findings provide new insights into the potential cellular targets for future treatments.

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Loss of the sulfate transporter Slc13a4 in placenta causes severe fetal abnormalities and death in mice

Cited by 18 publications

References 15 publications

Structure, organization and tissue expression of the pig SLC13A1 and SLC13A4 sulfate transporter genes

Structure, organization and tissue expression of the pig SLC13A1 and SLC13A4 sulfate transporter genes

Genetics and pathophysiology of mammalian sulfate biology

Dissecting the Impact of Maternal Androgen Exposure on Developmental Programming through Targeting the Androgen Receptor

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