The role of eutherian‐specific <i>RTL1</i> in the nervous system and its implications for the Kagami‐Ogata and Temple syndromes

Kitazawa, Moe; Sutani, Akito; Kaneko-Ishino, Tomoko; Ishino, Fumitoshi

doi:10.1111/gtc.12830

Cited by 26 publications

(38 citation statements)

References 49 publications

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“…PEG10 and RTL1 are expressed in many other tissues and organs besides the placenta ( Abed et al, 2019 ; Kitazawa et al, 2021 ). Recently, we demonstrated that mouse Rtl1 plays other important roles during the course of development, such as in fetal/neonatal skeletal muscle maturation as well as in functional activity of the central nervous system ( Kitazawa et al, 2020 , 2021 ). Therefore, it is possible that PEG10 has a multiplicity of functions across a range of organs and tissues.…”

Section: Resultsmentioning

confidence: 99%

PEG10 viral aspartic protease domain is essential for the maintenance of fetal capillary structure in the mouse placenta

et al. 2021

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The therian-specific gene paternally expressed 10 (Peg10) plays an essential role in placenta formation: Peg10 knockout mice exhibit early embryonic lethality as a result of severe placental defects. The PEG10 protein exhibits homology with long terminal repeat (LTR) retrotransposon GAG and POL proteins; therefore, we generated mice harboring a mutation in the highly conserved viral aspartic protease motif in the POL-like region of PEG10 because this motif is essential for the life cycle of LTR retrotransposons/retroviruses. Intriguingly, frequent perinatal lethality, not early embryonic lethality, was observed with fetal and placental growth retardation starting mid-gestation. In the mutant placentas, severe defects were observed in the fetal vasculature, where PEG10 is expressed in the three trophoblast cell layers that surround fetal capillary endothelial cells. Thus, Peg10 has essential roles, not only in early placenta formation, but also in placental vasculature maintenance from mid- to late-gestation. This implies that along the feto-maternal placenta interface an interaction occurs between two retrovirus-derived genes, Peg10 and retrotransposon Gag like 1 (Rtl1, also called Peg11), that is essential for the maintenance of fetal capillary endothelial cells.

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Section: Resultsmentioning

confidence: 99%

PEG10 viral aspartic protease domain is essential for the maintenance of fetal capillary structure in the mouse placenta

et al. 2021

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“…A series of KO mouse studies of mammalian-specific RVD genes, including Peg10 , Rtl1/Peg11 , and Ldoc1/Sirh7/Rtl7 , as well as other Rtl/Sirh genes, has demonstrated that they exert important functions in the placenta and/or brain in mice and presumably humans [ 24 , 25 , 26 , 27 , 28 , 29 , 30 ]. Thus, the concept of mammalian-specific genes acquired from retroviruses is evidently well-supported, providing a useful model for approaching a variety of mammalian-specific features related to viviparous reproduction and the highly developed central nervous system in terms of genomic function.…”

Section: Discussionmentioning

confidence: 99%

HERV-Derived Ervpb1 Is Conserved in Simiiformes, Exhibiting Expression in Hematopoietic Cell Lineages Including Macrophages

Matsuzawa

Lee

Nakagawa

et al. 2021

IJMS

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(1) Background: The ERVPb1 gene in humans is derived from an envelope (Env) gene of a human endogenous retrovirus group, HERV-P(b). The ERVPb1 gene reportedly has a conserved open reading frame (ORF) in Old World monkeys. Although its forced expression led to cell-fusion in an ex vivo cell culture system, like other Env-derived genes such as syncytin-1 and -2, its mRNA expression is not placenta-specific, but almost ubiquitous, albeit being quite low in human tissues and organs, implying a distinct role for ERVPb1. (2) Methods: To elucidate the cell lineage(s) in which the ERVPb1 protein is translated in human development, we developed a novel, highly sensitive system for detecting HERV-derived proteins/peptides expressed in the tissue differentiation process of human induced pluripotent stem cells (iPSCs). (3) Results: We first determined that ERVPb1 is also conserved in New World monkeys. Then, we showed that the ERVPb1 protein is translated from a uniquely spliced ERVPb1 transcript in hematopoietic cell lineages, including a subset of macrophages, and further showed that its mRNA expression is upregulated by lipopolysaccharide (LPS) stimulation in primary human monocytes. (4) Conclusions: ERVPb1 is unique to Simiiformes and actually translated in hematopoietic cell lineages, including a subset of macrophages.

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“…RTL1/PEG11 plays essential roles in the placenta, muscle and brain and is the major gene responsible for the Kagami-Ogata and Temple syndromes, two genomic imprinting diseases. It is located on human chromosome 14 ( Kagami et al, 2008 ; Sekita et al, 2008 , Kitazawa et al, 2017 , 2020 , 2021 ). Both overexpression and deficiency lead to abnormalities in the placenta as well as a variety of neuromuscular and/or psychiatric symptoms ( Kitazawa et al, 2020 , 2021 ).…”

Section: Novel Functions Provided By Newly Acquired Imprinted Genes I...mentioning

confidence: 99%

The Evolutionary Advantage in Mammals of the Complementary Monoallelic Expression Mechanism of Genomic Imprinting and Its Emergence From a Defense Against the Insertion Into the Host Genome

Kaneko-Ishino

Ishino

2022

Front. Genet.

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In viviparous mammals, genomic imprinting regulates parent-of-origin-specific monoallelic expression of paternally and maternally expressed imprinted genes (PEGs and MEGs) in a region-specific manner. It plays an essential role in mammalian development: aberrant imprinting regulation causes a variety of developmental defects, including fetal, neonatal, and postnatal lethality as well as growth abnormalities. Mechanistically, PEGs and MEGs are reciprocally regulated by DNA methylation of germ-line differentially methylated regions (gDMRs), thereby exhibiting eliciting complementary expression from parental genomes. The fact that most gDMR sequences are derived from insertion events provides strong support for the claim that genomic imprinting emerged as a host defense mechanism against the insertion in the genome. Recent studies on the molecular mechanisms concerning how the DNA methylation marks on the gDMRs are established in gametes and maintained in the pre- and postimplantation periods have further revealed the close relationship between genomic imprinting and invading DNA, such as retroviruses and LTR retrotransposons. In the presence of gDMRs, the monoallelic expression of PEGs and MEGs confers an apparent advantage by the functional compensation that takes place between the two parental genomes. Thus, it is likely that genomic imprinting is a consequence of an evolutionary trade-off for improved survival. In addition, novel genes were introduced into the mammalian genome via this same surprising and complex process as imprinted genes, such as the genes acquired from retroviruses as well as those that were duplicated by retropositioning. Importantly, these genes play essential/important roles in the current eutherian developmental system, such as that in the placenta and/or brain. Thus, genomic imprinting has played a critically important role in the evolutionary emergence of mammals, not only by providing a means to escape from the adverse effects of invading DNA with sequences corresponding to the gDMRs, but also by the acquisition of novel functions in development, growth and behavior via the mechanism of complementary monoallelic expression.

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The role of eutherian‐specific RTL1 in the nervous system and its implications for the Kagami‐Ogata and Temple syndromes

Cited by 26 publications

References 49 publications

PEG10 viral aspartic protease domain is essential for the maintenance of fetal capillary structure in the mouse placenta

PEG10 viral aspartic protease domain is essential for the maintenance of fetal capillary structure in the mouse placenta

HERV-Derived Ervpb1 Is Conserved in Simiiformes, Exhibiting Expression in Hematopoietic Cell Lineages Including Macrophages

The Evolutionary Advantage in Mammals of the Complementary Monoallelic Expression Mechanism of Genomic Imprinting and Its Emergence From a Defense Against the Insertion Into the Host Genome

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