Transcription factor AP-2γ is essential in the extra-embryonic lineages for early postimplantation development

The members of the AP-2 family of transcription factors play important roles during mammalian development and morphogenesis. AP-2γ (Tcfap2c – Mouse Genome Informatics) is a retinoic acid-responsive gene implicated in placental development and the progression of human breast cancer. We show that AP-2γ is present in all cells of preimplantation embryos and becomes restricted to the extra-embryonic lineages at the time of implantation. To study further the biological function of AP-2γ, we have generated Tcfap2c-deficient mice by gene disruption. The majority of Tcfap2c–/– mice failed to survive beyond 8.5 days post coitum (d.p.c.). At 7.5 d.p.c., Tcfap2c–/– mutants were typically arrested or retarded in their embryonic development in comparison to controls. Morphological and molecular analyses of mutants revealed that gastrulation could be initiated and that anterior-posterior patterning of the epiblast remained intact. However, the Tcfap2c mutants failed to establish a normal maternal-embryonic interface, and the extra-embryonic tissues were malformed. Moreover, the trophoblast-specific expression of eomesodermin and Cdx2, two genes implicated in FGF-responsive trophoblast stem cell maintenance, was significantly reduced. Chimera studies demonstrated that AP-2γ plays no major autonomous role in the development of the embryo proper. By contrast, the presence of AP-2γ in the extra-embryonic membranes is required for normal development of this compartment and also for survival of the mouse embryo.

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Differential mRNA expression of the phosphoprotein p19/SCG10 gene family in mouse preimplantation embryos, uterus, and placenta

Reproduction Fertility and Development ◽

10.1071/rd9920205 ◽

1992 ◽

Vol 4 (2) ◽

pp. 205 ◽

Cited By ~ 15

Author(s):

S Pampfer ◽

W Fan ◽

UK Schubart ◽

JW Pollard

Keyword(s):

Gene Family ◽

Mammalian Cells ◽

Developmental Stages ◽

Blastocyst Stage ◽

Northern Blotting ◽

Preimplantation Embryos ◽

Mammalian Development ◽

Specific Expression ◽

Developing Neurons ◽

Early Mammalian Development

The p19/SCG10 gene family encodes two structurally related cellular proteins that are implicated in signal transduction during differentiation of mammalian cells. Previous evidence suggests that both genes are expressed in a stage-specific manner but that expression of p19 is widespread, whereas that of SCG10 is restricted to developing neurons. To determine at which developmental stage these two genes are first expressed, we have probed for mRNA transcripts in preimplantation embryos and the utero-placental unit of the mouse. As determined by polymerase chain reaction (PCR) to amplify reverse-transcribed RNA, expression of both genes was detected in preimplantation embryos, although the temporal pattern was distinct. p19 mRNA appeared transiently in 2-cell embryos, was undetectable in morulae and early blastocysts and reappeared in expanded blastocysts. In contrast, embryonic expression of SCG10 mRNA commenced in morulae and was maintained through to the blastocyst stage. Interestingly, only SCG10 expression could be detected in blastocysts derived from cultures of 2-cell embryos. During the post-implantation period, SCG10 transcripts were only detected in the uterus and placenta by reverse transcriptase-PCR, whereas p19 mRNA could be detected by Northern blotting and showed stage-specific expression in both tissues. The data confirm that, at later developmental stages, expression of p19 is widespread while that of SCG10 is more restricted. The expression of both genes in preimplantation embryos suggests distinct but possibly overlapping roles for p19 and SCG10 in early mammalian development.

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323: Pravastatin improves pregnancy outcome and placental development in heme oxygenase-1 deficient mice

American Journal of Obstetrics and Gynecology ◽

10.1016/j.ajog.2017.10.259 ◽

2018 ◽

Vol 218 (1) ◽

pp. S202-S203

Author(s):

Abraham Tsur ◽

Flora Kalish ◽

Jordan Burgess ◽

Hui Zhao ◽

Kerriann Casey ◽

...

Keyword(s):

Pregnancy Outcome ◽

Heme Oxygenase ◽

Heme Oxygenase 1 ◽

Placental Development ◽

Deficient Mice

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Genomic imprinting in mouse blastocysts is predominantly associated with H3K27me3

Nature Communications ◽

10.1038/s41467-021-23510-4 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Laura Santini ◽

Florian Halbritter ◽

Fabian Titz-Teixeira ◽

Toru Suzuki ◽

Maki Asami ◽

...

Keyword(s):

Bisulfite Sequencing ◽

Blastocyst Stage ◽

Preimplantation Embryos ◽

Imprinted Genes ◽

Specific Expression ◽

Histone 3 ◽

Complex Program ◽

Genome Bisulfite Sequencing ◽

Mammalian Genomes ◽

Parent Of Origin

AbstractIn mammalian genomes, differentially methylated regions (DMRs) and histone marks including trimethylation of histone 3 lysine 27 (H3K27me3) at imprinted genes are asymmetrically inherited to control parentally-biased gene expression. However, neither parent-of-origin-specific transcription nor imprints have been comprehensively mapped at the blastocyst stage of preimplantation development. Here, we address this by integrating transcriptomic and epigenomic approaches in mouse preimplantation embryos. We find that seventy-one genes exhibit previously unreported parent-of-origin-specific expression in blastocysts (nBiX: novel blastocyst-imprinted expressed). Uniparental expression of nBiX genes disappears soon after implantation. Micro-whole-genome bisulfite sequencing (µWGBS) of individual uniparental blastocysts detects 859 DMRs. We further find that 16% of nBiX genes are associated with a DMR, whereas most are associated with parentally-biased H3K27me3, suggesting a role for Polycomb-mediated imprinting in blastocysts. nBiX genes are clustered: five clusters contained at least one published imprinted gene, and five clusters exclusively contained nBiX genes. These data suggest that early development undergoes a complex program of stage-specific imprinting involving different tiers of regulation.

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Tissue-specific expression of B7x protects from CD4 T cell–mediated autoimmunity

Journal of Experimental Medicine ◽

10.1084/jem.20100639 ◽

2011 ◽

Vol 208 (8) ◽

pp. 1683-1694 ◽

Cited By ~ 44

Author(s):

Joyce Wei ◽

P’ng Loke ◽

Xingxing Zang ◽

James P. Allison

Keyword(s):

T Cells ◽

Pancreatic Islets ◽

Peripheral Tolerance ◽

Wild Type ◽

Autoimmune Encephalomyelitis ◽

Specific Expression ◽

Tissue Specific ◽

Disease Induction ◽

Deficient Mice ◽

Experimental Autoimmune

B7x, an inhibitory member of the B7/CD28 superfamily, is highly expressed in a broad range of nonhematopoietic organs, suggesting a role in maintaining peripheral tolerance. As endogenous B7x protein is expressed in pancreatic islets, we investigated whether the molecule inhibits diabetogenic responses. Transfer of disease-inducing BDC2.5 T cells into B7x-deficient mice resulted in a more aggressive form of diabetes than in wild-type animals. This exacerbation of disease correlated with higher frequencies of islet-infiltrating Th1 and Th17 cells. Conversely, local B7x overexpression inhibited the development of autoimmunity, as crossing diabetes-susceptible BDC2.5/B6g7 mice to animals overexpressing B7x in pancreatic islets abrogated disease induction. This protection was caused by the inhibition of IFN-γ production by CD4 T cells and not to a skewing or expansion of Th2 or regulatory T cells. The suppressive function of B7x was also supported by observations from another autoimmune model, experimental autoimmune encephalomyelitis, in which B7x-deficient mice developed exacerbated disease in comparison with wild-type animals. Analysis of central nervous system–infiltrating immune cells revealed that the loss of endogenous B7x resulted in expanded Th1 and Th17 responses. Data from these two autoimmune models provide evidence that B7x expression in the periphery acts as an immune checkpoint to prevent tissue-specific autoimmunity.

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A γGT-AT1A receptor transgene protects renal cortical structure in AT1 receptor-deficient mice

Physiological Genomics ◽

10.1152/physiolgenomics.00120.2003 ◽

2004 ◽

Vol 18 (3) ◽

pp. 290-298 ◽

Cited By ~ 12

Author(s):

Thu H. Le ◽

Michael I. Oliverio ◽

Hyung-Suk Kim ◽

Harmony Salzler ◽

Rajesh C. Dash ◽

...

Keyword(s):

Blood Pressure ◽

Transgenic Mice ◽

Proximal Tubule ◽

Physiological Role ◽

Renal Proximal Tubule ◽

Hypoxanthine Phosphoribosyl Transferase ◽

Wild Type ◽

Specific Expression ◽

Low Levels ◽

Deficient Mice

To understand the physiological role of angiotensin type 1 (AT1) receptors in the proximal tubule of the kidney, we generated a transgenic mouse line in which the major murine AT1 receptor isoform, AT1A, was expressed under the control of the P1 portion of the γ-glutamyl transpeptidase (γGT) promoter. In transgenic mice, this promoter has been shown to confer cell-specific expression in epithelial cells of the renal proximal tubule. To avoid random integration of multiple copies of the transgene, we used gene targeting to produce mice with a single-copy transgene insertion at the hypoxanthine phosphoribosyl transferase ( Hprt) locus on the X chromosome. The physiological effects of the γGT-AT1A transgene were examined on a wild-type background and in mice with targeted disruption of one or both of the murine AT1 receptor genes ( Agtr1a and Agtr1b). On all three backgrounds, γGT-AT1A transgenic mice were healthy and viable. On the wild-type background, the presence of the transgene did not affect development, blood pressure, or kidney structure. Despite relatively low levels of expression in the proximal tubule, the transgene blunted the increase in renin expression typically seen in AT1-deficient mice and partially rescued the kidney phenotype associated with Agtr1a−/− Agtr1b−/− mice, significantly reducing cortical cyst formation by more than threefold. However, these low levels of cell-specific expression of AT1 receptors in the renal proximal tubule did not increase the low blood pressures or abolish sodium sensitivity, which are characteristic of AT1 receptor-deficient mice. Although our studies do not clearly identify a role for AT1 receptors in the proximal tubules of the kidney in blood pressure homeostasis, they support a major role for these receptors in modulating renin expression and in maintaining structural integrity of the renal cortex.

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pop-1/TCF, ref-2/ZIC and T-box factors regulate the development of anterior cells in the C. elegans embryo

10.1101/2021.12.14.472681 ◽

2021 ◽

Author(s):

Jonathan D Rumley ◽

Elicia A Preston ◽

Dylan Cook ◽

Felicia L Peng ◽

Amanda L Zacharias ◽

...

Keyword(s):

Wnt Pathway ◽

Expression Patterns ◽

Specific Expression ◽

T Box ◽

Animal Development ◽

C Elegans ◽

The Many ◽

Necessary And Sufficient ◽

Cell Division Timing ◽

Anterior Posterior

Patterning of the anterior-posterior axis is fundamental to animal development. The Wnt pathway plays a major role in this process by activating the expression of posterior genes in animals from worms to humans. This observation raises the question of whether the Wnt pathway or other regulators control the expression of the many anterior-expressed genes. We found that the expression of five anterior-specific genes in Caenorhabditis elegans embryos depends on the Wnt pathway effectors pop-1/TCF and sys-1/β-catenin. We focused further on one of these anterior genes, ref-2/ZIC, a conserved transcription factor expressed in multiple anterior lineages. Live imaging of ref-2 mutant embryos identified defects in cell division timing and position in anterior lineages. Cis-regulatory dissection identified three ref-2 transcriptional enhancers, one of which is necessary and sufficient for anterior-specific expression. This enhancer is activated by the T-box transcription factors TBX-37 and TBX-38, and surprisingly, concatemerized TBX-37/38 binding sites are sufficient to drive anterior-biased expression alone, despite the broad expression of TBX-37 and TBX-38. Taken together, our results highlight the diverse mechanisms used to regulate anterior expression patterns in the embryo.

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Specific expression of a retinoic acid-regulated, zinc-finger gene, Rex-1, in preimplantation embryos, trophoblast and spermatocytes

Development ◽

10.1242/dev.113.3.815 ◽

1991 ◽

Vol 113 (3) ◽

pp. 815-824 ◽

Cited By ~ 6

Author(s):

M.B. Rogers ◽

B.A. Hosler ◽

L.J. Gudas

Keyword(s):

Retinoic Acid ◽

Germ Cell ◽

Cell Fate ◽

Zinc Finger ◽

Zinc Finger Protein ◽

Inner Cell Mass ◽

Cell Mass ◽

Embryonic Stem ◽

Preimplantation Embryos ◽

Specific Expression

We have previously isolated a cDNA clone for a gene whose expression is reduced by retinoic acid (RA) treatment of F9 embryonal carcinoma cells. The nucleotide sequence indicated that this gene, Rex-1, encodes a zinc-finger protein and thus may be a transcriptional regulator. The Rex-1 message level is high in two lines of embryonic stem cells (CCE and D3) and is reduced when D3 cells are induced to differentiate using four different growth conditions. As expected for a stem-cell-specific message, Rex-1 mRNA is present in the inner cell mass (ICM) of the day 4.5 mouse blastocyst. It is also present in the polar trophoblast of the blastocyst. One and two days later, Rex-1 message is found in the ectoplacental cone and extraembryonic ectoderm of the egg cylinder (trophoblast-derived tissues), but its abundance is much reduced in the embryonic ectoderm which is directly descended from the ICM. Rex-1 is expressed in the day 18 placenta (murine gestation is 18 days), a tissue which is largely derived from trophoblast. The only tested adult tissue that contains detectable amounts of Rex-1 mRNA is the testis. In situ hybridization and northern analyses of RNA from germ-cell-deficient mouse testis and stage-specific germ cell preparations suggest that Rex-1 expression is limited to spermatocytes (germ cells undergoing meiosis). These results suggest that Rex-1 is involved in trophoblast development and spermatogenesis, and is a useful marker for studies of early cell fate determination in the ICM.

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Regulation of a dpp target gene in the Drosophila embryo

Development ◽

10.1242/dev.124.2.303 ◽

1997 ◽

Vol 124 (2) ◽

pp. 303-311 ◽

Cited By ~ 3

Author(s):

J. Rusch ◽

M. Levine

Keyword(s):

Target Gene ◽

Fusion Gene ◽

Drosophila Embryo ◽

Specific Expression ◽

Downstream Target ◽

Embryonic Tissues ◽

Posterior Midgut ◽

Downstream Target Gene ◽

Genetic Epistasis ◽

Vp16 Fusion

In Drosophila, two TGF-beta growth factors, dpp and screw, function synergistically to subdivide the dorsal ectoderm into two embryonic tissues, the amnioserosa and dorsal epidermis. Previous studies have shown that peak dpp activity is required for the localized expression of zerknullt (zen), which encodes a homeodomain transcription factor. We present evidence that zen directly activates the amnioserosa-specific expression of a downstream target gene, Race (Related to angiotensin converting enzyme). A 533 bp enhancer from the Race promoter region is shown to mediate selective expression in the amnioserosa, as well as the anterior and posterior midgut rudiments. This enhancer contains three zen protein binding sites, and mutations in these sites virtually abolish the expression of an otherwise normal Race-lacZ fusion gene in the amnioserosa, but not in the gut. Genetic epistasis experiments suggest that zen is not the sole activator of Race, although a hyperactivated form of zen (a zen-VP16 fusion protein) can partially complement reduced levels of dpp activity. These results suggest that dpp regulates multiple transcription factors, which function synergistically to specify the amnioserosa.

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Mouse Cdx-1 expression during gastrulation

Development ◽

10.1242/dev.117.1.191 ◽

1993 ◽

Vol 117 (1) ◽

pp. 191-203 ◽

Cited By ~ 13

Author(s):

B.I. Meyer ◽

P. Gruss

Keyword(s):

Spinal Cord ◽

Expression Pattern ◽

Early Development ◽

Primitive Streak ◽

Embryonic Axes ◽

Specific Expression ◽

Limb Buds ◽

Process Formation ◽

Spinal Cord Level ◽

Anterior Posterior

We describe the expression pattern of the mouse Cdx-1 gene during early development, examined by both RNA and protein analyses. Cdx-1 expression began with the onset of the head process formation (day 7.5) in ectodermal and mesodermal cells of the primitive streak. Expression extended initially to the middle of the prospective hindbrain and subsequently regressed caudad to the spinal cord level by day 9.5. The mesoderm-specific expression was detected in the first somites and could be followed during their differentiation to the myotome of the dorsal somitic edge by day 12. The developing limb buds and the mesonephros exhibited expression up to day 12. No signal could be detected in notochordal cells and cells of the definitive endoderm. Thus, Cdx-1 is expressed during gastrulation when anterior-posterior positional values are established along the embryonic axes. Furthermore, the expression correlates with the formation of segmented tissue in the posterior hindbrain, the spinal cord and structures like the mesonephros.

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Allelic H3K27me3 to allelic DNA methylation switch maintains noncanonical imprinting in extraembryonic cells

Science Advances ◽

10.1126/sciadv.aay7246 ◽

2019 ◽

Vol 5 (12) ◽

pp. eaay7246 ◽

Cited By ~ 12

Author(s):

Zhiyuan Chen ◽

Qiangzong Yin ◽

Azusa Inoue ◽

Chunxia Zhang ◽

Yi Zhang

Keyword(s):

Dna Methylation ◽

De Novo ◽

Genetic Manipulation ◽

Paternal Allele ◽

Gene Promoters ◽

Maternal Allele ◽

Mammalian Development ◽

Placental Development ◽

Early Embryos ◽

Allele Specific

Faithful maintenance of genomic imprinting is essential for mammalian development. While germline DNA methylation–dependent (canonical) imprinting is relatively stable during development, the recently found oocyte-derived H3K27me3-mediated noncanonical imprinting is mostly transient in early embryos, with some genes important for placental development maintaining imprinted expression in the extraembryonic lineage. How these noncanonical imprinted genes maintain their extraembryonic-specific imprinting is unknown. Here, we report that maintenance of noncanonical imprinting requires maternal allele–specific de novo DNA methylation [i.e., somatic differentially methylated regions (DMRs)] at implantation. The somatic DMRs are located at the gene promoters, with paternal allele–specific H3K4me3 established during preimplantation development. Genetic manipulation revealed that both maternal EED and zygotic DNMT3A/3B are required for establishing somatic DMRs and maintaining noncanonical imprinting. Thus, our study not only reveals the mechanism underlying noncanonical imprinting maintenance but also sheds light on how histone modifications in oocytes may shape somatic DMRs in postimplantation embryos.

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