Ctdp1 deficiency leads to early embryonic lethality in mice and defects in cell cycle progression in MEFs

• Published in: Biology open Vol. 10; no. 1
• Main Authors: Qiao, Fangfang, Law, Henry C-H, Krieger, Kimiko L, Clement, Emalie J, Xiao, Yi, Buckley, Shannon M, Woods, Nicholas T
• Format: Journal Article
• Language: English
• Published: England The Company of Biologists Ltd 01.01.2021; The Company of Biologists
• Subjects: Animals; Apoptosis; Body weight; Breast cancer; Cataracts; ccfdn; Cell cycle; Cell Cycle - genetics; cell cycle arrest; Cell Cycle Checkpoints - genetics; Cell death; Cell Death - genetics; Cell Line; Cell survival; ctdp1; Cyclin B; Deletion; DNA damage; DNA-directed RNA polymerase; Embryo fibroblasts; Embryonic Development - genetics; embryonic lethality; Embryos; Fibroblasts; Fibroblasts - metabolism; Flox; Gene Deletion; Gene regulation; Gene Targeting; Genes, Lethal; Genetic Vectors - genetics; Histone H3; Histones; Immunohistochemistry; knockout; Lethality; mefs; Mice; Mice, Knockout; Mortality; Mutation; Neuropathy; Phenotype; Phosphoprotein Phosphatases - deficiency; RNA polymerase; RNA polymerase II; MEFs; Ctdp1; Cell death; Embryonic lethality; Cell cycle arrest; Knockout; CCFDN
• ISSN: 2046-6390; 2046-6390
• DOI: 10.1242/bio.057232

RNA polymerase II subunit A Carboxy-Terminal Domain Phosphatase 1 (CTDP1), a member of the haloacid dehalogenase superfamily phosphatases, has a defined role in transcriptional regulation, but emerging evidence suggests an expanded functional repertoire in the cell cycle and DNA damage response. In humans, a splice site mutation in gives rise to the rare Congenital Cataracts Facial Dysmorphism and Neuropathy syndrome, and recent evidence from our lab indicates CTDP1 is required for breast cancer growth and proliferation. To explore the physiological function of CTDP1 in a mammalian system, we generated a conditional knockout mouse model by insertion of sites upstream of exon 3 and downstream of exon 4. Biallelic deletion of results in lethality before embryonic day 7.5, with morphological features indicating embryo cell death and resorption. However, mice are haplosufficient for phenotypic traits including body weight, hematological parameters, exploratory and locomotive functions. To investigate the potential mechanisms of the embryonic death caused by biallelic knockout, mouse embryonic fibroblasts (MEFs) were established from and mice. Lentivirus delivered Cre-mediated biallelic deletion of in MEFs results in cell death preceded by impaired proliferation characterized by an increase in G1- and G2-phase populations and a reduction in the S-phase population. These cell cycle alterations caused by deletion of are associated with an increase in p27 protein expression and a decrease in phosphorylated RB, phosphorylated Histone H3, and Cyclin B expression. Together, these results reveal that plays an essential role in early mouse embryo development and cell growth and survival in part by regulating the cell cycle.