title: Epiblast-specific loss of HCF-1 leads to failure in anterior-posterior axis specification.
abstract: Mammalian Host-Cell Factor 1 (HCF-1), a transcriptional co-regulator, plays important roles during the cell-division cycle in cell culture, embryogenesis as well as adult tissue. In mice, HCF-1 is encoded by the X-chromosome-linked Hcfc1 gene. Induced Hcfc1(cKO/+) heterozygosity with a conditional knockout (cKO) allele in the epiblast of female embryos leads to a mixture of HCF-1-positive and -deficient cells owing to random X-chromosome inactivation. These embryos survive owing to the replacement of all HCF-1-deficient cells by HCF-1-positive cells during E5.5 to E8.5 of development. In contrast, complete epiblast-specific loss of HCF-1 in male embryos, Hcfc1(epiKO/Y), leads to embryonic lethality. Here, we characterize this lethality. We show that male epiblast-specific loss of Hcfc1 leads to a developmental arrest at E6.5 with a rapid progressive cell-cycle exit and an associated failure of anterior visceral endoderm migration and primitive streak formation. Subsequently, gastrulation does not take place. We note that the pattern of Hcfc1(epiKO/Y) lethality displays many similarities to loss of β-catenin function. These results reveal essential new roles for HCF-1 in early embryonic cell proliferation and development.
authors: Center for Integrative Genomics, Génopode, University of Lausanne, 1015 Lausanne, Switzerland.
authors: Shilpi
authors: S
authors: Minocha
authors: Ecole Polytechnique Fédérale de Lausanne (EPFL) SV ISREC, Station 19, 1015 Lausanne, Switzerland.
authors: Sylvain
authors: S
authors: Bessonnard
authors: Center for Integrative Genomics, Génopode, University of Lausanne, 1015 Lausanne, Switzerland.
authors: Tzu-Ling
authors: TL
authors: Sung
authors: Center for Integrative Genomics, Génopode, University of Lausanne, 1015 Lausanne, Switzerland.
authors: Catherine
authors: C
authors: Moret
authors: Ecole Polytechnique Fédérale de Lausanne (EPFL) SV ISREC, Station 19, 1015 Lausanne, Switzerland. Electronic address: daniel.constam@epfl.ch.
authors: Daniel B
authors: DB
authors: Constam
authors: Center for Integrative Genomics, Génopode, University of Lausanne, 1015 Lausanne, Switzerland. Electronic address: winship.herr@unil.ch.
authors: Winship
authors: W
authors: Herr
mesh_terms: D000818:Animals; D019521:Body Patterning / Q000235:genetics*; D002453:Cell Cycle / Q000235:genetics; D002465:Cell Movement / Q000235:genetics*; D049109:Cell Proliferation / Q000235:genetics*; D047108:Embryonic Development / Q000235:genetics*; D004707:Endoderm / Q000166:cytology / Q000378:metabolism; D005260:Female; D054262:Gastrulation / Q000235:genetics; D018507:Gene Expression Regulation, Developmental; D050172:Genes, X-Linked / Q000235:genetics; D051863:Host Cell Factor C1 / Q000235:genetics*; D020287:In Situ Nick-End Labeling; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D015398:Signal Transduction; D051176:beta Catenin / Q000378:metabolism
chemical_list: C497693:Hcfc1 protein, mouse; D051863:Host Cell Factor C1; D051176:beta Catenin
keywords: AVE; Cell cycle; Embryonic lethality; Gastrulation; HCF-1/Hcfc1; Primitive streak