Lack of protein kinase C‐delta (PKCδ) disrupts fertilization and embryonic development

Ma, Wei; Baumann, Claudia; Viveiros, Maria M.

doi:10.1002/mrd.22528

Cited by 16 publications

(8 citation statements)

References 48 publications

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“…It also has been reported that the experiments with sperm from PKCδ KO male mice and oocytes from WT female mice resulted in lower fertilization rates and lower early cleavage rates [41]. However, in our study, results of in vitro fertilization with eggs from three WT females using one male PKCδ KO mouse spermatozoa showed no differences from WT male spermatozoa when comparing fertilization rates and developmental conditions up to two cells.…”

Section: Plos Onecontrasting

confidence: 69%

PKCδ deficiency inhibits fetal development and is associated with heart elastic fiber hyperplasia and lung inflammation in adult PKCδ knockout mice

et al. 2021

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Protein kinase C-delta (PKCδ) has a caspase-3 recognition sequence in its structure, suggesting its involvement in apoptosis. In addition, PKCδ was recently reported to function as an anti-cancer factor. The generation of a PKCδ knockout mouse model indicated that PKCδ plays a role in B cell homeostasis. However, the Pkcrd gene, which is regulated through complex transcription, produces multiple proteins via alternative splicing. Since gene mutations can result in the loss of function of molecular species required for each tissue, in the present study, conditional PKCδ knockout mice lacking PKCδI, II, IV, V, VI, and VII were generated to enable tissue-specific deletion of PKCδ using a suitable Cre mouse. We generated PKCδ-null mice that lacked whole-body expression of PKCδ. PKCδ+/- parental mice gave birth to only 3.4% PKCδ-/- offsprings that deviated significantly from the expected Mendelian ratio (χ2(2) = 101.7, P < 0.001). Examination of mice on embryonic day 11.5 (E11.5) showed the proportion of PKCδ-/- mice implanted in the uterus in accordance with Mendelian rules; however, approximately 70% of the fetuses did not survive at E11.5. PKCδ-/- mice that survived until adulthood showed enlarged spleens, with some having cardiac and pulmonary abnormalities. Our findings suggest that the lack of PKCδ may have harmful effects on fetal development, and heart and lung functions after birth. Furthermore, our study provides a reference for future studies on PKCδ deficient mice that would elucidate the effects of the multiple protein variants in mice and decipher the roles of PKCδ in various diseases.

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Section: Plos Onecontrasting

confidence: 69%

PKCδ deficiency inhibits fetal development and is associated with heart elastic fiber hyperplasia and lung inflammation in adult PKCδ knockout mice

et al. 2021

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“…While loss of PKCδ has been reported to reduce fertility, post-natal development of PKCδ−/− mice appears to be normal (Ma, Baumann, & Viveiros, 2015), although subtle developmental phenotypes have been reported. For instance, we show a transient delay in mammary gland development in PKCδ−/− mice, including reduced ductal branching (Allen-Petersen et al, 2010).…”

Section: Biological Functions Of Pkcδmentioning

confidence: 99%

Multifunctional roles of PKCδ: Opportunities for targeted therapy in human disease

Reyland

Jones

2016

Pharmacology & Therapeutics

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The serine–threonine protein kinase, protein kinase C-δ (PKCδ), is emerging as a bi-functional regulator of cell death and proliferation. Studies in PKCδ−/− mice have confirmed a pro-apoptotic role for this kinase in response to DNA damage and a tumor promoter role in some oncogenic contexts. In non-transformed cells, inhibition of PKCδ suppresses the release of cytochrome c and caspase activation, indicating a function upstream of apoptotic pathways. Data from PKCδ−/− mice demonstrate a role for PKCδ in the execution of DNA damage-induced and physiologic apoptosis. This has led to the important finding that inhibitors of PKCδ can be used therapeutically to reduce irradiation and chemotherapy-induced toxicity. By contrast, PKCδ is a tumor promoter in mouse models of mammary gland and lung cancer, and increased PKCδ expression is a negative prognostic indicator in Her2+ and other subtypes of human breast cancer. Understanding how these distinct functions of PKCδ are regulated is critical for the design of therapeutics to target this pathway. This review will discuss what is currently known about biological roles of PKCδ and prospects for targeting PKCδ in human disease.

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“…It is conceivable that the hyperactivation of Ras affects survival of spermatids and contributes to a higher sperm count yet lower quality sperm. Activation of ERK is associated with reduction in sperm quality [21] and alterations in sperm quality are known to reduce the number of offspring produced [41, 42]. The presence of abnormal spermatid morphology such as atypical residual bodies in the spermatids of Nf1 +/- mice further supports the hypothesis that Nf1 +/- mice produce lower quality sperm.…”

Section: Discussionmentioning

confidence: 99%

Neurofibromin haploinsufficiency results in altered spermatogenesis in a mouse model of neurofibromatosis type 1

et al. 2018

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The fertility of men with neurofibromatosis 1 (NF1) is reduced. Despite this observation, gonadal function has not been examined in patients with NF1. In order to assess the role of reduced neurofibromin in the testes, we examined testicular morphology and function in an Nf1+/- mouse model. We found that although Nf1+/- male mice are able to reproduce, they have significantly fewer pups per litter than Nf1+/+ control males. Reduced fertility in Nf1+/- male mice is associated with disorganization of the seminiferous epithelium, with exfoliation of germ cells and immature spermatids into the tubule lumen. Morphometric analysis shows that these alterations are associated with decreased Leydig cell numbers and increased spermatid cell numbers. We hypothesized that hyper-activation of Ras in Nf1+/- males affects ectoplasmic specialization, a Sertoli-spermatid adherens junction involved in spermiation. Consistent with this idea, we found increased expression of phosphorylated ERK, a downstream effector of Ras that has been shown to alter ectoplasmic specialization, in Nf1+/- males in comparison to control Nf1+/+ littermates. These data demonstrate that neurofibromin haploinsufficiency impairs spermatogenesis and fertility in a mouse model of NF1.

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Lack of protein kinase C‐delta (PKCδ) disrupts fertilization and embryonic development

Cited by 16 publications

References 48 publications

PKCδ deficiency inhibits fetal development and is associated with heart elastic fiber hyperplasia and lung inflammation in adult PKCδ knockout mice

PKCδ deficiency inhibits fetal development and is associated with heart elastic fiber hyperplasia and lung inflammation in adult PKCδ knockout mice

Multifunctional roles of PKCδ: Opportunities for targeted therapy in human disease

Neurofibromin haploinsufficiency results in altered spermatogenesis in a mouse model of neurofibromatosis type 1

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