Cincinnati Childrens Research Foundation

Cincinnati, OH, United States

Cincinnati Childrens Research Foundation

Cincinnati, OH, United States
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Aprikyan A.A.,Institute for Nanotechnology and Stem Cell Biology | Khuchua Z.,Cincinnati Childrens Research Foundation
British Journal of Haematology | Year: 2013

Barth syndrome (BTHS) is an X-linked autosomal recessive disorder characterized by neutropenia, cardiomyopathy and growth retardation. BTHS was first described as mitochondrial disease affecting neutrophils as well as cardiac and skeletal muscles. Patients with neutropenia may have extremely low levels of circulating neutrophils and suffer from recurring sometimes life-threatening bacterial infections. Sepsis is not infrequent, may occur unexpectedly in a patient with no history for pronounced bacterial infections and may lead to death. The reduced level of circulating neutrophils suggests either a reduced production of myeloid cells in the bone marrow and premature apoptosis or aberrant clearance of neutrophils in peripheral blood. The underlying molecular defects are truncation, deletion or substitution mutations in the TAZ gene that appear to result in loss-of-function of the gene product tafazzin. Molecular mechanisms triggering neutropenia and cardiomyopathy in BTHS remain largely unclear. The current review focusses on recent advances in the understanding of molecular and cellular bases of neutropenia in Barth syndrome and covers the functional implications of the TAZ mutations, experimental models for neutropenia, the specific cellular abnormalities triggered by loss of TAZ function and potential novel therapeutic strategies for restoring the normal phenotype. © 2013 Blackwell Publishing Ltd.

Kim J.,Harvard University | Oh W.-J.,Harvard University | Gaiano N.,Johns Hopkins University | Yoshida Y.,Cincinnati Childrens Research Foundation | Gu C.,Harvard University
Genes and Development | Year: 2011

Blood vessel networks are typically formed by angiogenesis, a process in which new vessels form by sprouting of endothelial cells from pre-existing vessels. This process is initiated by vascular endothelial growth factor (VEGF)- mediated tip cell selection and subsequent angiogenic sprouting. Surprisingly, we found that VEGF directly controls the expression of Plexin-D1, the receptor for the traditional repulsive axon guidance cue, semaphorin 3E (Sema3E). Sema3E-Plexin-D1 signaling then negatively regulates the activity of the VEGF-induced Delta-like 4 (Dll4)-Notch signaling pathway, which controls the cell fate decision between tip and stalk cells. Using the mouse retina as a model system, we show that Plexin-D1 is selectively expressed in endothelial cells at the front of actively sprouting blood vessels and its expression is tightly controlled by VEGF secreted by surrounding tissues. Therefore, although the Sema3E secreted by retinal neurons is evenly distributed throughout the retina, Sema3E- Plexin-D1 signaling is spatially controlled by VEGF through its regulation of Plexin-D1. Moreover, we show that gain and loss of function of Sema3E and Plexin-D1 disrupts normal Dll4 expression, Notch activity, and tip/stalk cell distribution in the retinal vasculature. Finally, the retinal vasculature of mice lacking sema3E or plexin-D1 has an uneven growing front, a less-branched vascular network, and abnormal distribution of dll4-positive cells. Lowering Notch activity in the mutant mice can reverse this defect, solidifying the observation that Dll4-Notch signaling is regulated by Sema3E-Plexin-D1 and is required for its function in vivo. Together, these data reveal a novel role of Sema3E-Plexin-D1 function in modulating angiogenesis via a VEGF-induced feedback mechanism. © 2011 by Cold Spring Harbour Laboratory Press.

Steinhoff M.C.,Cincinnati Childrens Research Foundation
Vaccine | Year: 2013

The strategy of prenatal maternal immunization to protect the pregnant woman and her infant was first used with tetanus toxoid, when it was recognized that young infants had very high rates of tetanus disease, well before the age when infant immunizations are provided. Antenatal immunization has now been recommended and utilized for additional vaccines to prevent infections in pregnancy and the young infant.There are several issues to consider which are unique to the strategy of antenatal immunization. The first is that immunization of the pregnant woman will affect the woman who receives the vaccine, her developing fetus, and the young infant for several months after delivery. For this discussion, we will consider the availability of data for the maternal-fetal-infant triad in 4 aspects:. (1)Immunogenicity.(2)Safety.(3)Infant immunosuppression caused by passive maternal antibody.(4)Effectiveness.This discussion will review available data from vaccines for prevention of tetanus, pneumococcal, influenza and pertussis infections used in antenatal maternal immunization programs. © 2013 Elsevier Ltd.

Liu J.,Cincinnati Childrens Research Foundation
Fly | Year: 2011

In a recent publication, we identified a novel F-box protein, encoded by fates-shifted (fsd), that plays a role in targeting Bcd for ubiquitination and degradation. Our analysis of mutant Drosophila embryos suggests that Bcd protein degradation is important for proper gradient formation and developmental fate specification. Here we describe further experiments that lead to an estimate of Bcd half-life, < 15 min, in embryos during the time of gradient formation. We use our findings to evaluate different models of Bcd gradient formation. With this new estimate, we simulate the Bcd gradient formation process in our own biologically realistic 2-D model. Finally, we discuss the role of Bcd-encoded positional information in controlling the positioning and precision of developmental decisions.

Katoh H.,Arizona State University | Wang D.,Arizona State University | Daikoku T.,Cincinnati Childrens Research Foundation | Sun H.,Arizona State University | And 3 more authors.
Cancer Cell | Year: 2013

A large body of evidence indicates that chronic inflammation is one of several key risk factors for cancer initiation, progression, and metastasis. However, the underlying mechanisms responsible for the contribution of inflammation and inflammatory mediators to cancer remain elusive. Here, we present genetic evidence that loss of CXCR2 dramatically suppresses chronic colonic inflammation and colitis-associated tumorigenesis through inhibiting infiltration of myeloid-derived suppressor cells (MDSCs) into colonic mucosa and tumors in a mouse model of colitis-associated cancer. CXCR2 ligands were elevated in inflamed colonic mucosa and tumors and induced MDSC chemotaxis. Adoptive transfer of wild-type MDSCs into Cxcr2-/- mice restored AOM/DSS-induced tumor progression. MDSCs accelerated tumor growth by inhibiting CD8+ Tcell cytotoxic activity. © 2013 Elsevier Inc.

Li Y.,Cincinnati Childrens Research Foundation | Sun X.,Cincinnati Childrens Research Foundation | Dey S.K.,Cincinnati Childrens Research Foundation
Cell Reports | Year: 2015

During implantation, uterine luminal epithelial (LE) cells first interact with the blastocyst trophectoderm. Within 30hr after the initiation of attachment, LE cells surrounding the blastocyst in the implantation chamber (crypt) disappear, allowing trophoblast cells to make direct physical contact with the underneath stroma for successful implantation. The mechanism for the extraction of LE cells was thought to be mediated by apoptosis. Here, we show that LE cells in direct contact with the blastocyst are endocytosed by trophoblast cells by adopting the nonapoptotic cell-in-cell invasion process (entosis) in the absence of caspase 3 activation. Our invivo observations were reinforced by the results of co-culture experiments with primary uterine epithelial cells with trophoblast stem cells or blastocysts showing internalization of epithelial cells by trophoblasts. We have identified entosis as a mechanism to remove LE cells by trophoblast cells in implantation, conferring a role for entosis in an important physiological process. © 2015 The Authors.

Liu J.,Cincinnati Childrens Research Foundation | Ma J.,Cincinnati Childrens Research Foundation
Nature Cell Biology | Year: 2011

Bicoid (Bcd) is a morphogenetic protein that instructs patterning along the anteriorposterior (AP) axis in Drosophila melanogaster embryos. Despite extensive studies, what controls the formation of a normal concentration gradient of Bcd remains an unresolved and controversial question. Here, we show that Bcd protein degradation is mediated by the ubiquitin-proteasome pathway. We have identified an F-box protein, encoded by fates-shifted (fsd), that has an important role in Bcd protein degradation by targeting it for ubiquitylation. Embryos from females lacking fsd have an altered Bcd gradient profile, resulting in a shift of the fatemap along the AP axis. Our study is an experimental demonstration that, contrary to an alternative hypothesis, Bcd protein degradation is required for normal gradient formation and developmental fate determination. © 2011 Macmillan Publishers Limited. All rights reserved.

Cha J.,Cincinnati Childrens Research Foundation | Dey S.K.,Cincinnati Childrens Research Foundation
Seminars in Cell and Developmental Biology | Year: 2014

Embryo implantation in eutherian mammals is a highly complex process and requires reciprocal communication between different cell types of the embryo at the blastocyst stage and receptive uterus. The events of implantation are dynamic and highly orchestrated over a species-specific period of time with distinctive and overlapping expression of many genes. Delayed implantation in different species has helped elucidate some of the intricacies of implantation timing and different modes of the implantation process. How these events are coordinated in time and space are not clearly understood. We discuss potential regulators of the precise timing of these events with respect to central and local clock mechanisms. This review focuses on the timing and synchronization of early pregnancy events in mouse and consequences of their aberrations at later stages of pregnancy. © 2014 Elsevier Ltd.

Filippi M.-D.,Cincinnati Childrens Research Foundation
Blood | Year: 2014

In this issue of Blood, Taylor et al uncovered a novel role for serum response factor (SRF) in neutrophil migration to inflamed tissues. Unexpectedly, SRF controls neutrophil migration via CD11b integrin clustering and trafficking. © 2014 by The American Society of Hematology.

Liu J.,Cincinnati Childrens Research Foundation | Ma J.,Cincinnati Childrens Research Foundation
Nature Communications | Year: 2013

The Drosophila morphogen gradient of Bicoid (Bcd) initiates anterior-posterior (AP) patterning; however, it is poorly understood how its ability to activate a target gene may have an impact on this process. Here we report an F-box protein, Dampened (Dmpd) as a nuclear cofactor of Bcd that can enhance its activating potency. We establish a quantitative platform to specifically investigate two parameters of a Bcd target gene response, expression amplitude and boundary position. We show that embryos lacking Dmpd have a reduced amplitude of Bcd-activated hunchback (hb) expression at a critical time of development. This is because of a reduced Bcd-dependent transcribing probability. This defect is faithfully propagated further downstream of the AP-patterning network to alter the spatial characteristics of even-skipped (eve) stripes. Thus, unlike another Bcd-interacting F-box protein Fate-shifted (Fsd), which controls AP patterning through regulating the Bcd gradient profile, Dmpd achieves its patterning role through regulating the activating potency of Bcd. © 2013 Macmillan Publishers Limited.

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