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Pregnancy Timeline by SemestersDevelopmental TimelineFertilizationFirst TrimesterSecond TrimesterThird TrimesterFirst Thin Layer of Skin AppearsEnd of Embryonic PeriodEnd of Embryonic PeriodFemale Reproductive SystemBeginning Cerebral HemispheresA Four Chambered HeartFirst Detectable Brain WavesThe Appearance of SomitesBasic Brain Structure in PlaceHeartbeat can be detectedHeartbeat can be detectedFinger and toe prints appearFinger and toe prints appearFetal sexual organs visibleBrown fat surrounds lymphatic systemBone marrow starts making blood cellsBone marrow starts making blood cellsInner Ear Bones HardenSensory brain waves begin to activateSensory brain waves begin to activateFetal liver is producing blood cellsBrain convolutions beginBrain convolutions beginImmune system beginningWhite fat begins to be madeHead may position into pelvisWhite fat begins to be madePeriod of rapid brain growthFull TermHead may position into pelvisImmune system beginningLungs begin to produce surfactant
CLICK ON weeks 0 - 40 and follow along every 2 weeks of fetal development


Gene mutation may explain female infertility

Researchers at Baylor College of Medicine, Texas Children's Hospital and Rice University have uncovered a gene mutation that may provide answers to unexplained female infertility.

"Experts cannot identify the cause in an estimated 10 to 15 percent of couples with infertility — and 50 percent of women with recurrent pregnancy loss. Research has found mutations that lead to loss-of-function in some genes of the NLRP family, can cause women to fail to reproduce. Reasons may include abnormally developing placentas, loss of the embryo before implantation, or — more rarely — a baby born with developmental disabilities," says Ignatia B. Van den Veyver MD, professor in the department of obstetrics and gynecology, Baylor College of Medicine, Texas.

The subcortical maternal complex (SCMC) is part of the protein and molecules, all maternal in origin, packed inside an egg as it prepares for fertilization. After the egg is fertilized and begins to divide, for a short period of time it relies heavily on these stored proteins and compounds for essential functions — including DNA methylation — until its new genes made from the mix of mother and father's DNA, switch on.

"From prior studies by us and others, we knew DNA gene methylation normally occurrs when mom passes genes on, but is absent in pregnancies of women with NLRP7 gene mutations. Methylation is a small chemical modification of DNA that controls which genes are expressed (function) and which will not."

Ignatia B. Van den Veyver MD, Professor and Vice Chair for Research, Department of Obstetrics and Gynecology, Baylor College of Medicine; Century Scholars Program, Rice University; Jan and Duncan Neurological Research Institute, Texas Children’s Hospital, all of Houston, Texas, USA, and senior author.

"Women carrying these mutations are healthy in all other physical aspects, so they are unaware that they have mutations which will not allow them to carry a pregnancy," says first author Sangeetha Mahadevan PhD, a graduate of the Translational Biology and Molecular Medicine program at Baylor and currently a postdoctoral fellow in the Van den Veyver lab. "So, we developed a mouse model to investigate mechanisms by which inactivation of human NLRP2 and NLRP7 genes might affect reproductive success and fertility.

When we genetically engineered mice to lack the Nlrp2 gene, the animals looked completely normal. However, after mating we observed three different types of outcomes. Some (1) did not get pregnant, others (2) had stillborn pups with abnormalities and (3) a third group gave birth to live pups of normal appearance, but fewer pups per litter — and some of the pups were smaller or larger than expected," Mahadevan added.

In the mouse model lacking the gene Nlrp2, scientists also saw abnormal DNA methylation in their pups, inducing them to draw strong parallels between human and mouse systems. Although mice only carry the Nlrp2 gene, researchers hypothesize this gene might be covering the roles of both NLRP2 and NLRP7 in humans.

"There was a spectrum of reproductive outcomes when females lacked the Nlrp2 gene. However, when male mice lacked the gene, there was no impact on fertility or offspring."

Sangeetha Mahadevan PhD, Department of Obstetrics and Gynecology, Baylor College of Medicine; Century Scholars Program, Rice University; Shared Equipment Authority, Rice University, all of Houston, Texas, USA

The study appears in Scientific Reports, a member of the Nature family of journals.

Van den Veyver adds, "Initially we thought we had to focus on the nucleus of the cell and proteins that carry out methylation. We discovered that NLRP2 proteins are mostly outside the nucleus, though inside the egg, in the subcortical maternal complex (SCMC)."

"We also found that when the Nlrp2 gene is absent or inactive in the mother, the SCMC does not form properly in the egg. One of the proteins that plays a role in DNA methylation, seems not to be in the right place in early embryos. This might explain the disturbances in DNA methylation observed in offspring of female mice lacking Nlrp2."

Sangeetha Mahadevan PhD

Van den Veyver: "Finding NLRP2 proteins in the SCMC was not unexpected but this is the first time scientific evidence shows NLRP2 proteins are part of this important cellular complex, giving more support to the idea that SCMC is critical for fertility and embryonic development."

Researchers also investigated whether the lack of Nlrp2 in mouse eggs would affect their survival when cultured in a lab — relevant to in vitro fertilization.

Mahadevan: "When we attempted growing mouse eggs of a female carrying the Nlrp2 gene mutation in an artificial environment, they did not develop. This has implications for in vitro fertilization. There will be women who may not be candidates for this procedure. Their embryos would likely be unable to grow in culture as a result of their mutations in NLRP genes."

Mammalian parental genomes contribute differently to early embryonic development. Before activation of the zygotic genome, the maternal genome provides all transcripts and proteins required for the transition from a highly specialized oocyte to a pluripotent embryo. Depletion of these maternally-encoded transcripts frequently results in failure of preimplantation embryonic development, but their functions in this process are incompletely understood. We found that female mice lacking NLRP2 are subfertile because of early embryonic loss and the production of fewer offspring that have a wide array of developmental phenotypes and abnormal DNA methylation at imprinted loci. By demonstrating that NLRP2 is a member of the subcortical maternal complex (SCMC), an essential cytoplasmic complex in oocytes and preimplantation embryos with poorly understood function, we identified imprinted postzygotic DNA methylation maintenance, likely by directing subcellular localization of proteins involved in this process, such as DNMT1, as a new crucial role of the SCMC for mammalian reproduction.

Other authors that contributed to this work include Varsha Sathappan and Budi Utama from Rice University, and Isabel Lorenzo and Khalied Kaskar from Baylor.

Parts of this project were supported by the National Institutes of Health (grants R01HD079442, P30CA125123). This project was also supported in part by the Intellectual and Developmental Disabilities Research Center (grant number 1U54 HD083092 from the Eunice Kennedy Shriver National Institute of Child Health & Human Development) and by the National Center for Research Resources (C06RR029965).
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Mar 22, 2017   Fetal Timeline   Maternal Timeline   News   News Archive   

Mouse eggs carrying the Nlrp2 gene mutation, when fertilized in the lab, did not develop.
So women with mutations in their NLRP genes may not be candidates for in-vitro fertilization.

Image Credit: Public Domain


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