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The imprinted Igf2-Igf2r axis is critical for matching placental microvasculature expansion to fetal growth.

ABSTRACT: In all eutherian mammals, growth of the fetus is dependent upon a functional placenta, but whether and how the latter adapts to putative fetal signals is currently unknown. Here, we demonstrate, through fetal, endothelial, hematopoietic, and trophoblast-specific genetic manipulations in the mouse, that endothelial and fetus-derived IGF2 is required for the continuous expansion of the feto-placental microvasculature in late pregnancy. The angiocrine effects of IGF2 on placental microvasculature expansion are mediated, in part, through IGF2R and angiopoietin-Tie2/TEK signaling. Additionally, IGF2 exerts IGF2R-ERK1/2-dependent pro-proliferative and angiogenic effects on primary feto-placental endothelial cells ex vivo. Endothelial and fetus-derived IGF2 also plays an important role in trophoblast morphogenesis, acting through Gcm1 and Synb. Thus, our study reveals a direct role for the imprinted Igf2-Igf2r axis on matching placental development to fetal growth and establishes the principle that hormone-like signals from the fetus play important roles in controlling placental microvasculature and trophoblast morphogenesis.

SUBMITTER: Sandovici I

PROVIDER: S-EPMC8751640 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Placental imprinting of SLC22A3 in the IGF2R imprinted domain is conserved in therian mammals.

Project description:BackgroundThe eutherian IGF2R imprinted domain is regulated by an antisense long non-coding RNA, Airn, which is expressed from a differentially methylated region (DMR) in mice. Airn silences two neighbouring genes, Solute carrier family 22 member 2 (Slc22a2) and Slc22a3, to establish the Igf2r imprinted domain in the mouse placenta. Marsupials also have an antisense non-coding RNA, ALID, expressed from a DMR, although the exact function of ALID is currently unknown. The eutherian IGF2R DMR is located in intron 2, while the marsupial IGF2R DMR is located in intron 12, but it is not yet known whether the adjacent genes SLC22A2 and/or SLC22A3 are also imprinted in the marsupial lineage. In this study, the imprinting status of marsupial SLC22A2 and SLC22A3 in the IGF2R imprinted domain in the chorio-vitelline placenta was examined in a marsupial, the tammar wallaby.ResultsIn the tammar placenta, SLC22A3 but not SLC22A2 was imprinted. Tammar SLC22A3 imprinting was evident in placental tissues but not in the other tissues examined in this study. A putative promoter of SLC22A3 lacked DNA methylation, suggesting that this gene is not directly silenced by a DMR on its promoter as seen in the mouse. Based on immunofluorescence, we confirmed that the tammar SLC22A3 is localised in the endodermal cell layer of the tammar placenta where nutrient trafficking occurs.ConclusionsSince SLC22A3 is imprinted in the tammar placenta, we conclude that this placental imprinting of SLC22A3 has been positively selected after the marsupial and eutherian split because of the differences in the DMR location. Since SLC22A3 is known to act as a transporter molecule for nutrient transfer in the eutherian placenta, we suggest it was strongly selected to control the balance between supply and demand of nutrients in marsupial as it does in eutherian placentas.

| S-EPMC9419357 | biostudies-literature

Fetus-derived IGF2 matches placental development to fetal demand

Project description:This SuperSeries is composed of the SubSeries listed below.

2020-07-01 | GSE125434 | GEO

Functional evolution of IGF2:IGF2R domain 11 binding generates novel structural interactions and a specific IGF2 antagonist.

Project description:Among the 15 extracellular domains of the mannose 6-phosphate/insulin-like growth factor-2 receptor (M6P/IGF2R), domain 11 has evolved a binding site for IGF2 to negatively regulate ligand bioavailability and mammalian growth. Despite the highly evolved structural loops of the IGF2:domain 11 binding site, affinity-enhancing AB loop mutations suggest that binding is modifiable. Here we examine the extent to which IGF2:domain 11 affinity, and its specificity over IGF1, can be enhanced, and we examine the structural basis of the mechanistic and functional consequences. Domain 11 binding loop mutants were selected by yeast surface display combined with high-resolution structure-based predictions, and validated by surface plasmon resonance. We discovered previously unidentified mutations in the ligand-interacting surface binding loops (AB, CD, FG, and HI). Five combined mutations increased rigidity of the AB loop, as confirmed by NMR. When added to three independently identified CD and FG loop mutations that reduced the koff value by twofold, these mutations resulted in an overall selective 100-fold improvement in affinity. The structural basis of the evolved affinity was improved shape complementarity established by interloop (AB-CD) and intraloop (FG-FG) side chain interactions. The high affinity of the combinatorial domain 11 Fc fusion proteins functioned as ligand-soluble antagonists or traps that depleted pathological IGF2 isoforms from serum and abrogated IGF2-dependent signaling in vivo. An evolved and reengineered high-specificity M6P/IGF2R domain 11 binding site for IGF2 may improve therapeutic targeting of the frequent IGF2 gain of function observed in human cancer.

| S-EPMC4878476 | biostudies-literature

Fetus-derived IGF2 matches placental development to fetal demand [microarray]

Project description:We used microarrays to identify genes that are transcriptionally dysregulated between Igf2EpiKO mutants and littermates controls at E19

2020-07-01 | GSE125278 | GEO

Fetus-derived IGF2 matches placental development to fetal demand [RNA-seq]

Project description:We used transcriptome analysis to identify genes transcriptionally disregulated in feto-placental endothelial cells from mutants with conditional deletion of Igf2 gene driven by the Meox2Cre.

2020-07-01 | GSE125351 | GEO

An exon splice enhancer primes IGF2:IGF2R binding site structure and function evolution.

Project description:Placental development and genomic imprinting coevolved with parental conflict over resource distribution to mammalian offspring. The imprinted genes IGF2 and IGF2R code for the growth promoter insulin-like growth factor 2 (IGF2) and its inhibitor, mannose 6-phosphate (M6P)/IGF2 receptor (IGF2R), respectively. M6P/IGF2R of birds and fish do not recognize IGF2. In monotremes, which lack imprinting, IGF2 specifically bound M6P/IGF2R via a hydrophobic CD loop. We show that the DNA coding the CD loop in monotremes functions as an exon splice enhancer (ESE) and that structural evolution of binding site loops (AB, HI, FG) improved therian IGF2 affinity. We propose that ESE evolution led to the fortuitous acquisition of IGF2 binding by M6P/IGF2R that drew IGF2R into parental conflict; subsequent imprinting may then have accelerated affinity maturation.

| S-EPMC4658703 | biostudies-literature

Association of birth weight with polymorphisms in the IGF2, H19, and IGF2R genes.

Project description:There is a substantial genetic component for birth weight variation. We tested 18 single nucleotide polymorphisms (SNPs) in the IGF2, H19, and IGF2R genes for associations with birth weight variation in 342 mother-newborn pairs (birth weight 2.1-4.7 kg at term) and 527 parent-newborn trios (birth weight 2.1-5.1 kg) across three localities. SNPs in the IGF2R (rs8191754; maternal genotype), IGF2 (rs3741205; newborn genotype), and 5' region of the H19 (rs2067051, rs2251375, and rs4929984) genes were associated with birth weight. Detailed analyses to distinguish direct maternal, direct newborn, and parent of origin effects for the most strongly associated H19 SNP (rs4929984) determined that the association of maternal genotype with newborn birth weight was due to parent of origin effects not direct maternal effects. That SNP is located near the CTCF binding sites that influence expression of the maternally imprinted IGF2 and paternally imprinted H19 locus, and there are statistically significant and independent opposite effects of the same rs4929984 allele, depending on the parent from which it was inherited.

| S-EPMC3063315 | biostudies-literature

Fetus-derived IGF2 matches placental development to fetal demand II [RNA-seq]

2021-07-31 | GSE179549 | GEO

Dysregulated H19/Igf2 expression disrupts cardiac-placental axis during development of Silver-Russell syndrome-like mouse models

Project description:Dysregulation of the imprinted H19/IGF2 locus can lead to Silver-Russell syndrome (SRS) in humans. However, the mechanism of how abnormal H19/IGF2 expression contributes to various SRS phenotypes remains unclear, largely due to incomplete understanding of the developmental functions of these two genes. We previously generated a mouse model with humanized H19/IGF2 imprinting control region (hIC1) on the paternal allele that exhibited H19/Igf2 dysregulation together with SRS-like growth restriction and perinatal lethality. Here, we dissect the role of H19 and Igf2 in cardiac and placental development utilizing multiple mouse models with varying levels of H19 and Igf2. We report severe cardiac defects such as ventricular septal defects and thinned myocardium, placental anomalies including thrombosis and vascular malformations, together with growth restriction in mouse embryos that correlated with the extent of H19/Igf2 dysregulation. Transcriptomic analysis using cardiac endothelial cells of these mouse models shows that H19/Igf2 dysregulation disrupts pathways related to extracellular matrix and proliferation of endothelial cells. Our work links the heart and placenta through regulation by H19 and Igf2, demonstrating that accurate dosage of both H19 and Igf2 is critical for normal embryonic development, especially related to the cardiac-placental axis.

| S-EPMC9704805 | biostudies-literature

Placental imprinted gene expression mediates the effects of maternal psychosocial stress during pregnancy on fetal growth.

Project description:Imprinted genes uniquely drive and support fetoplacental growth by controlling the allocation of maternal resources to the fetus and affecting the newborn's growth. We previously showed that alterations of the placental imprinted gene expression are associated with suboptimal perinatal growth and respond to environmental stimuli including socio-economic determinants. At the same time, maternal psychosocial stress during pregnancy (MPSP) has been shown to affect fetal growth. Here, we set out to test the hypothesis that placental imprinted gene expression mediates the effects of MPSP on fetal growth in a well-characterized birth cohort, the Stress in Pregnancy (SIP) Study. We observed that mothers experiencing high MPSP deliver infants with lower birthweight (P=0.047). Among the 109 imprinted genes tested, we detected panels of placental imprinted gene expression of 23 imprinted genes associated with MPSP and 26 with birthweight. Among these genes, five imprinted genes (CPXM2, glucosidase alpha acid (GAA), GPR1, SH3 and multiple ankyrin repeat domains 2 (SHANK2) and THSD7A) were common to the two panels. In multivariate analyses, controlling for maternal age and education and gestational age at birth and infant gender, two genes, GAA and SHANK2, each showed a 22% mediation of MPSP on fetal growth. These data provide new insights into the role that imprinted genes play in translating the maternal stress message into a fetoplacental growth pattern.

| S-EPMC6786904 | biostudies-literature

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