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Biomedical subjects

Miguel Constância

Publications and source records attributed to Miguel Constância.

6 recordsLinked to original sources
PubMed2005

Adaptation of nutrient supply to fetal demand in the mouse involves interaction between the Igf2 gene and placental transporter systems.

The mammalian fetus is unique in its dependence during gestation on the supply of maternal nutrients through the placenta. Maternal supply and fetal demand for nutrients need to be fine tuned for healthy growth and development of the fetus along its genetic trajectory. An altered balance between supply and demand can lead to deviations from this trajectory with long-term consequences for health. We have previously shown that in a knockout lacking the imprinted placental-specific Igf2 transcript (P0), growth of the placenta is compromised from early gestation but fetal growth is normal until late gestation, suggesting functional adaptation of the placenta to meet the fetal demands. Here, we show that placental transport of glucose and amino acids are increased in the Igf2 P0(+/-) null and that this up-regulation of transport occurs, at least in part, through increased expression of the transporter genes Slc2a3 and Slc38a4, the imprinted member of the System A amino acid transporter gene family. Decreasing fetal demand genetically by removal of fetal Igf2 abolished up-regulation of both transport systems and reduced placental System A amino acid transport activity and expression of Slc38a2 in late gestation. Our results provide direct evidence that the placenta can respond to fetal demand signals through regulation of expression of specific placental transport systems. Thus, crosstalk between an imprinted growth demand gene (Igf2) and placental supply transporter genes (Slc38a4, Slc38a2, and Slc2a3) may be a component of the genetic control of nutrient supply and demand during mammalian development.

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PubMed2003

Epigenetic modifications in an imprinting cluster are controlled by a hierarchy of DMRs suggesting long-range chromatin interactions.

Imprinted genes and their control elements occur in clusters in the mammalian genome and carry epigenetic modifications. Observations from imprinting disorders suggest that epigenetic modifications throughout the clusters could be under regional control. However, neither the elements that are responsible for regional control, nor its developmental timing, particularly whether it occurs in the germline or postzygotically, are known. Here we examine regional control of DNA methylation in the imprinted Igf2-H19 region in the mouse. Paternal germline specific methylation was reprogrammed after fertilization in two differentially methylated regions (DMRs) in Igf2, and was reestablished after implantation. Using a number of knockout strains in the region, we found that the DMRs themselves are involved in regional coordination in a hierarchical fashion. Thus the H19 DMR was needed on the maternal allele to protect the Igf2 DMRs 1 and 2 from methylation, and Igf2 DMR1 was needed to protect DMR2 from methylation. This regional coordination occurred exclusively after fertilization during somatic development, and did not involve linear spreading of DNA methylation, suggesting a model in which long-range chromatin interactions are involved in regional epigenetic coordination. These observations are likely to be relevant to other gene clusters in which epigenetic regulation plays a role, and in pathological situations in which epigenetic regulation is disrupted.

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PubMed2003

Regulation of supply and demand for maternal nutrients in mammals by imprinted genes.

The placenta has evolved in eutherian mammals primarily to provide nutrients for the developing fetus. The genetic control of the regulation of supply and demand for maternal nutrients is not understood. In this review we argue that imprinted genes have central roles in controlling both the fetal demand for, and the placental supply of, maternal nutrients. Recent studies on Igf2 (insulin-like growth factor 2) knockout mouse models provide experimental support for this hypothesis. These show effects on placental transport capacity consistent with a role of IGF-II in modulating both the placental supply and fetal demand for nutrients. Imprinting of genes with such functions may have coevolved with the placenta and new evidence suggests that transporter proteins, as well as the regulators themselves, may also be imprinted. These data and hypotheses are important, as deregulation of supply and demand affects fetal growth and has long term consequences for health in mammals both in the neonatal period and, as a result of fetal programming, in adulthood.

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PubMed2002

Placental-specific IGF-II is a major modulator of placental and fetal growth.

Imprinted genes in mammals are expressed from only one of the parental chromosomes, and are crucial for placental development and fetal growth. The insulin-like growth factor II gene (Igf2) is paternally expressed in the fetus and placenta. Here we show that deletion from the Igf2 gene of a transcript (P0) specifically expressed in the labyrinthine trophoblast of the placenta leads to reduced growth of the placenta, followed several days later by fetal growth restriction. The fetal to placental weight ratio is thus increased in the absence of the P0 transcript. We show that passive permeability for nutrients of the mutant placenta is decreased, but that secondary active placental amino acid transport is initially upregulated, compensating for the decrease in passive permeability. Later the compensation fails and fetal growth restriction ensues. Our study provides experimental evidence for imprinted gene action in the placenta that directly controls the supply of maternal nutrients to the fetus, and supports the genetic conflict theory of imprinting. We propose that the Igf2 gene, and perhaps other imprinted genes, control both the placental supply of, and the genetic demand for, maternal nutrients to the mammalian fetus.

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PubMed2002

Proliferation and growth factor expression in abnormally enlarged placentas of mouse interspecific hybrids.

It has been shown previously that abnormal placental growth occurs in crosses and backcrosses between different mouse (Mus) species. In such crosses, late gestation placentas may weigh between 13 and 848 mg compared with a mean placental weight of approximately 100 mg in late gestation M. musculus intraspecific crosses. A locus on the X-chromosome was shown to segregate with placental dysplasia. Thus in the (M. musculus x M. spretus)F1 x M. musculus backcross, placental hyperplasia cosegregates with a M. spretus derived X-chromosome. Here we have investigated whether increased cell proliferation and aberrant expression of two genes that are involved in placental growth control, Igf2 and Esx1, may cause, or contribute to placental hyperplasia. Increased bromodeoxyuridine labeling of nuclei, reflecting enhanced proliferation, was indeed observed in hyperplastic placentas when compared with normal littermate placentas. Also, increased expression of Igf2 was seen in giant cells and spongiotrophoblast. However, when M. musculus x M. spretus F1 females were backcrossed with males that were heterozygous for a targeted mutation of the Igf2 gene, placentas that carried a M. spretus derived X-chromosome and were negative for a functional Igf2 allele exhibited an intermediate placental phenotype. Furthermore, in early developmental stages of placental hyperplasia, we observed a decreased expression of the X-chromosomal Esx1 gene. This finding suggests that abnormal expression of both Igf2 and Esx1 contributes to abnormal placental development in mouse interspecific hybrids. However, Esx1 is not regulated by IGF2.

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