Alpha-fetoprotein, the major fetal serum protein, is not essential for embryonic development but is required for female fertility

Gabant, Philippe; Forrester, Lesley M.; Nichols, Jennifer; Reeth, Thierry Van; Mees, Christelle De; Pajack, Bernard; Watt, Alistair J.; Smitz, Johan; Alexandre, Henri; Szpirer, Claude; Szpirer, Josiane

doi:10.1073/pnas.202215399

Cited by 93 publications

(87 citation statements)

References 44 publications

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“…See SI Methods for detail. LZB20KO mice were repeatedly crossed to AFP-deficient mice (AFP tm1/bmm , C57BL/6 background), which harbor the LacZ gene in the AFP mutant allele driven by the AFP promoter (2). Animal experiments were done following institutional guidelines.…”

Section: Methodsmentioning

confidence: 99%

“…To this end, we took advantage of the AFP mutant mice harboring the LacZ reporter gene in the AFP locus under the control of AFP P1 promoter (2), which allowed us to assess the transcriptional activity of the AFP gene by X-Gal staining. Consistent with nearly complete repression of AFP gene transcription, ␤-galactosidase was undetectable in the adult liver from AFP single mutant mice (Fig.…”

Section: Dysregulation Of Afp In Livermentioning

confidence: 99%

“…AFP is required for female fertility during embryonic development by protecting the developing female brain from prenatal exposure to estrogen (2,3). Shortly after birth, the AFP gene is dramatically repressed to extremely low levels, which in liver represents a nearly 10,000-fold reduction of transcription (4).…”

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confidence: 99%

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Zinc finger protein ZBTB20 is a key repressor of alpha-fetoprotein gene transcription in liver

Xie¹,

Hai²,

Tsai

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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The alpha-fetoprotein (AFP) gene is highly activated in fetal liver but is dramatically repressed shortly after birth. The mechanisms that underlie AFP transcriptional repression in postpartum liver are not well understood. AFP enhancer, repressor region, and promoter are implicated to be involved in AFP postnatal repression, but the major transcriptional repressor remains undefined. We previously identified a zinc finger protein gene ZBTB20. To determine its physiological functions in vivo, we have generated hepatocyte-specific ZBTB20 knockout mice by the Cre/loxP approach and demonstrated here that ZBTB20 ablation in liver led to dramatic derepression of the AFP gene in entire liver throughout adult life, although the hepatocytes were normally under nonproliferating status. Furthermore, we found that ZBTB20 was a transcriptional repressor capable of specifically inhibiting AFP promoter-driven transcriptional activity. Liver chromatin immunoprecipitation and mobility shift assays showed that ZBTB20 bound to AFP promoter directly. ZBTB20 was developmentally activated in liver after birth and inversely correlated with its AFP gene expression, suggesting that activated ZBTB20 expression in liver mediated AFP gene repression. Our data point to ZBTB20 as a key regulator governing AFP gene transcription and postulate a new model for the postnatal gene repression of AFP in liver.gene regulation ͉ transcription factor ͉ transcriptional repressor

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Section: Methodsmentioning

confidence: 99%

Section: Dysregulation Of Afp In Livermentioning

confidence: 99%

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Zinc finger protein ZBTB20 is a key repressor of alpha-fetoprotein gene transcription in liver

Xie¹,

Hai²,

Tsai

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

121

167

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“…Afp gene knockout (AFP KO) mice have been generated by Gabant and coworkers (21). The mice homozygous for the targeted allele are viable and develop normally, but females are sterile due to anovulation.…”

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confidence: 99%

Alpha-Fetoprotein Controls Female Fertility and Prenatal Development of the Gonadotropin-Releasing Hormone Pathway through an Antiestrogenic Action

Mees

Laes²,

Bakker

et al. 2006

Molecular and Cellular Biology

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It has been shown previously that female mice homozygous for an alpha-fetoprotein (AFP) null allele are sterile as a result of anovulation, probably due to a defect in the hypothalamic-pituitary axis. Here we show that these female mice exhibit specific anomalies in the expression of numerous genes in the pituitary, including genes involved in the gonadotropin-releasing hormone pathway, which are underexpressed. In the hypothalamus, the gonadotropin-releasing hormone gene, Gnrh1, was also found to be down-regulated. However, pituitary gene expression could be normalized and fertility could be rescued by blocking prenatal estrogen synthesis using an aromatase inhibitor. These results show that AFP protects the developing female brain from the adverse effects of prenatal estrogen exposure and clarify a long-running debate on the role of this fetal protein in brain sexual differentiation.The alpha-fetoprotein (AFP) gene is a member of the albumin gene family and encodes a serum glycoprotein with an oncofetal pattern of expression. AFP is produced in high concentrations during embryonic life by the hepatocytes and the visceral endoderm of the yolk sac and to a lesser extent by the developing gastrointestinal tract and kidney (2,26,39). Its synthesis decreases dramatically shortly after birth to reach trace amounts a few weeks later but can be restored during life when liver pathologies or some types of tumors develop (hepatitis, cirrhosis, hepatoma, teratocarcinoma, and some pancreatic and renal tumors) (1,11,26,27,31,39).The exact function of AFP has been the subject of a longrunning debate. One important feature of AFP is its capacity to bind estrogens, but not androgens, at its C-terminal extremity with a K a of 10 9 M Ϫ1 (33,35,43), indicating that it can act as an estrogen carrier in the blood. Although human AFP has not been demonstrated to bind estrogens, human AFP peptides do so and human AFP possesses an antiestrogenic activity (7, 44). Human AFP could thus be involved in antiestrogenic effects, just like rodent AFP. Because perinatal exposure to estrogens in rodent females results in anovulatory sterility associated with altered gonadotropin production (16,23,29), it is classically assumed that the function of AFP is to sequester circulating estrogens and, by so doing, to protect the developing female brain from their effects (for a review, see reference 32). Alternatively, because AFP is found inside neurons without being produced locally, it has been suggested that AFP has more than a passive neuroprotective role and specifically delivers estrogens into certain brain cells in order to ensure correct female brain differentiation (18,41).Afp gene knockout (AFP KO) mice have been generated by Gabant and coworkers (21). The mice homozygous for the targeted allele are viable and develop normally, but females are sterile due to anovulation. Reciprocal transfer experiments with ovarian tissue have demonstrated that the ovaries are functional but lack an adequate signal from the hypothalamicpituitary axis to exe...

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“…However, whereas mutant homozygous adult males were viable and fertile, as we also observed for the mutation-homozygous father in pedigree A, AFP-null females mice were infertile by a dysfunction of the hypothalamic/pituitary system, leading to anovulation. 25 Although we did not get an infertility history from the affected families, the homozygous females have not yet reached fertility age and will need to be evaluated thoroughly.…”

Section: Discussionmentioning

confidence: 97%

Congenital deficiency of alpha feto-protein

2004

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Alpha-fetoprotein (AFP) is the main fetus serum glycoprotein with a very low concentration in the adult. AFP deficiency is a rare phenomenon. We studied two families with congenital AFP deficiency and searched for mutations in the AFP gene. We identified one mutation of 2 base deletion in exon 8, in both families, that leads to the congenital deficiency of AFP. The mutation nt930-931delCT (T294fs25X) creates a frameshift after codon 294 that leads to a stop codon after 24 amino acids, thus truncating the normal length of AFP of 609 amino acids. All the affected children were found to be homozygous for the mutation as was one of the fathers. The affected individuals were asymptomatic and presented normal development. This first identification of a mutation in the AFP gene demonstrates for the first time that deficiency of AFP is compatible with human normal fetal development and further reproduction in males.

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Alpha-fetoprotein, the major fetal serum protein, is not essential for embryonic development but is required for female fertility

Cited by 93 publications

References 44 publications

Zinc finger protein ZBTB20 is a key repressor of alpha-fetoprotein gene transcription in liver

Zinc finger protein ZBTB20 is a key repressor of alpha-fetoprotein gene transcription in liver

Alpha-Fetoprotein Controls Female Fertility and Prenatal Development of the Gonadotropin-Releasing Hormone Pathway through an Antiestrogenic Action

Congenital deficiency of alpha feto-protein

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