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Article ; Online: Integrating Enhancer Mechanisms to Establish a Hierarchical Blood Development Program.

Mehta, Charu / Johnson, Kirby D / Gao, Xin / Ong, Irene M / Katsumura, Koichi R / McIver, Skye C / Ranheim, Erik A / Bresnick, Emery H

Cell reports

2017 Volume 20, Issue 12, Page(s) 2966–2979

Abstract: Hematopoietic development requires the transcription factor GATA-2, and GATA-2 mutations cause diverse pathologies, including leukemia. GATA-2-regulated enhancers increase Gata2 expression in hematopoietic stem/progenitor cells and control hematopoiesis. ...

Abstract	Hematopoietic development requires the transcription factor GATA-2, and GATA-2 mutations cause diverse pathologies, including leukemia. GATA-2-regulated enhancers increase Gata2 expression in hematopoietic stem/progenitor cells and control hematopoiesis. The +9.5-kb enhancer activates transcription in endothelium and hematopoietic stem cells (HSCs), and its deletion abrogates HSC generation. The -77-kb enhancer activates transcription in myeloid progenitors, and its deletion impairs differentiation. Since +9.5
Language	English
Publishing date	2017-09-19
Publishing country	United States
Document type	Journal Article
ZDB-ID	2649101-1
ISSN	2211-1247 ; 2211-1247
ISSN (online)	2211-1247
ISSN	2211-1247
DOI	10.1016/j.celrep.2017.08.090
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Dissecting Regulatory Mechanisms Using Mouse Fetal Liver-Derived Erythroid Cells.

McIver, Skye C / Hewitt, Kyle J / Gao, Xin / Mehta, Charu / Zhang, Jing / Bresnick, Emery H

Methods in molecular biology (Clifton, N.J.)

2017 Volume 1698, Page(s) 67–89

Abstract: Multipotent hematopoietic stem cells differentiate into an ensemble of committed progenitor cells that produce the diverse blood cells essential for life. Physiological mechanisms governing hematopoiesis, and mechanistic aberrations underlying non- ... ...

Abstract	Multipotent hematopoietic stem cells differentiate into an ensemble of committed progenitor cells that produce the diverse blood cells essential for life. Physiological mechanisms governing hematopoiesis, and mechanistic aberrations underlying non-malignant and malignant hematologic disorders, are often very similar in mouse and man. Thus, mouse models provide powerful systems for unraveling mechanisms that control hematopoietic stem/progenitor cell (HSPC) function in their resident microenvironments in vivo. Ex vivo systems, involving the culture of HSPCs generated in vivo, allow one to dissociate microenvironment-based and cell intrinsic mechanisms, and therefore have considerable utility. Dissecting mechanisms controlling cellular proliferation and differentiation is facilitated by the use of primary cells, since mutations and chromosome aberrations in immortalized and cancer cell lines corrupt normal mechanisms. Primary erythroid precursor cells can be expanded or differentiated in culture to yield large numbers of progeny at discrete maturation stages. We described a robust method for isolation, culture, and analysis of primary mouse erythroid precursor cells and their progeny.
MeSH term(s)	Animals ; Biomarkers ; Cell Culture Techniques ; Cell Cycle/genetics ; Cell Differentiation ; Cell Line ; Erythroid Cells/cytology ; Erythroid Cells/metabolism ; Erythroid Precursor Cells/cytology ; Erythroid Precursor Cells/metabolism ; Erythropoiesis/genetics ; Fetus ; Gene Expression ; Gene Expression Regulation, Developmental ; Genetic Vectors/genetics ; Humans ; Immunomagnetic Separation ; Immunophenotyping ; Liver/cytology ; Mice ; RNA, Small Interfering/genetics ; Retroviridae/genetics ; Signal Transduction ; Transduction, Genetic
Chemical Substances	Biomarkers ; RNA, Small Interfering
Language	English
Publishing date	2017-10-26
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ISSN	1940-6029
ISSN (online)	1940-6029
DOI	10.1007/978-1-4939-7428-3_4
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Article ; Online: Exosome complex orchestrates developmental signaling to balance proliferation and differentiation during erythropoiesis.

McIver, Skye C / Katsumura, Koichi R / Davids, Elsa / Liu, Peng / Kang, Yoon-A / Yang, David / Bresnick, Emery H

eLife

2016 Volume 5

Abstract: Since the highly conserved exosome complex mediates the degradation and processing of multiple classes of RNAs, it almost certainly controls diverse biological processes. How this post-transcriptional RNA-regulatory machine impacts cell fate decisions ... ...

Abstract	Since the highly conserved exosome complex mediates the degradation and processing of multiple classes of RNAs, it almost certainly controls diverse biological processes. How this post-transcriptional RNA-regulatory machine impacts cell fate decisions and differentiation is poorly understood. Previously, we demonstrated that exosome complex subunits confer an erythroid maturation barricade, and the erythroid transcription factor GATA-1 dismantles the barricade by transcriptionally repressing the cognate genes. While dissecting requirements for the maturation barricade in
Language	English
Publishing date	2016-08-20
Publishing country	England
Document type	Journal Article
ZDB-ID	2687154-3
ISSN	2050-084X ; 2050-084X
ISSN (online)	2050-084X
ISSN	2050-084X
DOI	10.7554/eLife.17877
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Article ; Online: Awakening the oocyte: controlling primordial follicle development.

McLaughlin, Eileen A / McIver, Skye C

Reproduction (Cambridge, England)

2009 Volume 137, Issue 1, Page(s) 1–11

Abstract: Oocytes are sequestered in primordial follicles before birth and remain quiescent in the ovary, often for decades, until recruited into the growing pool throughout the reproductive years. Therefore, activation of follicle growth is a major biological ... ...

Abstract	Oocytes are sequestered in primordial follicles before birth and remain quiescent in the ovary, often for decades, until recruited into the growing pool throughout the reproductive years. Therefore, activation of follicle growth is a major biological checkpoint that controls female reproductive potential. However, we are only just beginning to elucidate the cellular mechanisms required for either maintenance of the quiescent primordial follicle pool or initiation of follicle growth. Understanding the intracellular signalling systems that control oocyte maintenance and activation has significant implications for improving female reproductive productivity and longevity in mammals, and has application in domestic animal husbandry, feral animal population control and infertility in women.
MeSH term(s)	Animals ; Female ; Fertility/physiology ; Growth Substances/physiology ; Humans ; Oocytes/cytology ; Oogenesis/physiology ; Ovarian Follicle/growth & development ; Ovarian Follicle/physiology ; Phosphatidylinositol 3-Kinases/physiology ; Signal Transduction/physiology
Chemical Substances	Growth Substances ; Phosphatidylinositol 3-Kinases (EC 2.7.1.-)
Language	English
Publishing date	2009-01
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2034501-X
ISSN	1741-7899 ; 1470-1626 ; 1476-3990
ISSN (online)	1741-7899
ISSN	1470-1626 ; 1476-3990
DOI	10.1530/REP-08-0118
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Article ; Online: Exosome complex orchestrates developmental signaling to balance proliferation and differentiation during erythropoiesis

Skye C McIver / Koichi R Katsumura / Elsa Davids / Peng Liu / Yoon-A Kang / David Yang / Emery H Bresnick

eLife, Vol

2016 Volume 5

Abstract	Since the highly conserved exosome complex mediates the degradation and processing of multiple classes of RNAs, it almost certainly controls diverse biological processes. How this post-transcriptional RNA-regulatory machine impacts cell fate decisions and differentiation is poorly understood. Previously, we demonstrated that exosome complex subunits confer an erythroid maturation barricade, and the erythroid transcription factor GATA-1 dismantles the barricade by transcriptionally repressing the cognate genes. While dissecting requirements for the maturation barricade in Mus musculus, we discovered that the exosome complex is a vital determinant of a developmental signaling transition that dictates proliferation/amplification versus differentiation. Exosome complex integrity in erythroid precursor cells ensures Kit receptor tyrosine kinase expression and stem cell factor/Kit signaling, while preventing responsiveness to erythropoietin-instigated signals that promote differentiation. Functioning as a gatekeeper of this developmental signaling transition, the exosome complex controls the massive production of erythroid cells that ensures organismal survival in homeostatic and stress contexts.
Keywords	erythroid ; progenitor ; signaling ; transcription ; Medicine ; R ; Science ; Q ; Biology (General) ; QH301-705.5
Language	English
Publishing date	2016-08-01T00:00:00Z
Publisher	eLife Sciences Publications Ltd
Document type	Article ; Online
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Article: The rise of testicular germ cell tumours: the search for causes, risk factors and novel therapeutic targets.

McIver, Skye C / Roman, Shaun D / Nixon, Brett / Loveland, Kate L / McLaughlin, Eileen A

F1000Research

2013 Volume 2, Page(s) 55

Abstract: Since the beginning of the 20th century there has been a decline in the reproductive vitality of men within the Western world. The declining sperm quantity and quality has been associated with increased overt disorders of sexual development including ... ...

Abstract	Since the beginning of the 20th century there has been a decline in the reproductive vitality of men within the Western world. The declining sperm quantity and quality has been associated with increased overt disorders of sexual development including hypospadias, undescended testes and type II testicular germ cell tumours (TGCTs). The increase in TGCTs cannot be accounted for by genetic changes in the population. Therefore exposure to environmental toxicants appears to be a major contributor to the aetiology of TGCTs and men with a genetic predisposition are particularly vulnerable. In particular, Type II TGCTs have been identified to arise from a precursor lesion Carcinoma in situ (CIS), identified as a dysfunctional gonocyte; however, the exact triggers for CIS development are currently unknown. Therefore the transition from gonocytes into spermatogonia is key to those studying TGCTs. Recently we have identified seven miRNA molecules (including members of the miR-290 family and miR-136, 463* and 743a) to be significantly changed over this transition period. These miRNA molecules are predicted to have targets within the CXCR4, PTEN, DHH, RAC and PDGF pathways, all of which have important roles in germ cell migration, proliferation and homing to the spermatogonial stem cell niche. Given the plethora of potential targets affected by each miRNA molecule, subtle changes in miRNA expression could have significant consequences e.g. tumourigenesis. The role of non-traditional oncogenes and tumour suppressors such as miRNA in TGCT is highlighted by the fact that the majority of these tumours express wild type p53, a pivotal tumour suppressor usually inactivated in cancer. While treatment of TGCTs is highly successful, the impact of these treatments on fertility means that identification of exact triggers, earlier diagnosis and alternate treatments are essential. This review examines the genetic factors and possible triggers of type II TGCT to highlight target areas for potential new treatments.
Language	English
Publishing date	2013-02-19
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	2699932-8
ISSN	2046-1402
ISSN	2046-1402
DOI	10.12688/f1000research.2-55.v1
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Article ; Online: Integrating Enhancer Mechanisms to Establish a Hierarchical Blood Development Program.

Mehta, Charu / Johnson, Kirby D / Gao, Xin / Ong, Irene / Katsumura, Koichi Ricardo / McIver, Skye Courtney / Ranheim, Erik A / Bresnick, Emery H

Blood

2020 Volume 130, Issue Suppl_1, Page(s) 7

Abstract: Disclosures: No relevant conflicts of interest to declare. ...

Abstract	Disclosures: No relevant conflicts of interest to declare.
Language	English
Publishing date	2020-01-14
Publishing country	United States
Document type	Journal Article
ZDB-ID	80069-7
ISSN	1528-0020 ; 0006-4971
ISSN (online)	1528-0020
ISSN	0006-4971
DOI	10.1182/blood.V130.Suppl_1.7.7
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Article ; Online: Integrating Enhancer Mechanisms to Establish a Hierarchical Blood Development Program

Charu Mehta / Kirby D. Johnson / Xin Gao / Irene M. Ong / Koichi R. Katsumura / Skye C. McIver / Erik A. Ranheim / Emery H. Bresnick

Cell Reports, Vol 20, Iss 12, Pp 2966-

2017 Volume 2979

Abstract	Hematopoietic development requires the transcription factor GATA-2, and GATA-2 mutations cause diverse pathologies, including leukemia. GATA-2-regulated enhancers increase Gata2 expression in hematopoietic stem/progenitor cells and control hematopoiesis. The +9.5-kb enhancer activates transcription in endothelium and hematopoietic stem cells (HSCs), and its deletion abrogates HSC generation. The −77-kb enhancer activates transcription in myeloid progenitors, and its deletion impairs differentiation. Since +9.5−/− embryos are HSC deficient, it was unclear whether the +9.5 functions in progenitors or if GATA-2 expression in progenitors solely requires −77. We further dissected the mechanisms using −77;+9.5 compound heterozygous (CH) mice. The embryonic lethal CH mutation depleted megakaryocyte-erythrocyte progenitors (MEPs). While the +9.5 suffices for HSC generation, the −77 and +9.5 must reside on one allele to induce MEPs. The −77 generated burst-forming unit-erythroid through the induction of GATA-1 and other GATA-2 targets. The enhancer circuits controlled signaling pathways that orchestrate a GATA factor-dependent blood development program.
Keywords	GATA-2 ; enhancer ; hematopoiesis ; erythroid ; myeloid ; progenitor ; mouse model ; Biology (General) ; QH301-705.5
Subject code	570
Language	English
Publishing date	2017-09-01T00:00:00Z
Publisher	Elsevier
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: The rise of testicular germ cell tumours

Skye C McIver / Shaun D Roman / Brett Nixon / Kate L Loveland / Eileen A McLaughlin

F1000Research, Vol

the search for causes, risk factors and novel therapeutic targets [v1; ref status: indexed, http://f1000r.es/md]

2013 Volume 2

Abstract	Since the beginning of the 20th century there has been a decline in the reproductive vitality of men within the Western world. The declining sperm quantity and quality has been associated with increased overt disorders of sexual development including hypospadias, undescended testes and type II testicular germ cell tumours (TGCTs). The increase in TGCTs cannot be accounted for by genetic changes in the population. Therefore exposure to environmental toxicants appears to be a major contributor to the aetiology of TGCTs and men with a genetic predisposition are particularly vulnerable. In particular, Type II TGCTs have been identified to arise from a precursor lesion Carcinoma in situ (CIS), identified as a dysfunctional gonocyte; however, the exact triggers for CIS development are currently unknown. Therefore the transition from gonocytes into spermatogonia is key to those studying TGCTs. Recently we have identified seven miRNA molecules (including members of the miR-290 family and miR-136, 463* and 743a) to be significantly changed over this transition period. These miRNA molecules are predicted to have targets within the CXCR4, PTEN, DHH, RAC and PDGF pathways, all of which have important roles in germ cell migration, proliferation and homing to the spermatogonial stem cell niche. Given the plethora of potential targets affected by each miRNA molecule, subtle changes in miRNA expression could have significant consequences e.g. tumourigenesis. The role of non-traditional oncogenes and tumour suppressors such as miRNA in TGCT is highlighted by the fact that the majority of these tumours express wild type p53, a pivotal tumour suppressor usually inactivated in cancer. While treatment of TGCTs is highly successful, the impact of these treatments on fertility means that identification of exact triggers, earlier diagnosis and alternate treatments are essential. This review examines the genetic factors and possible triggers of type II TGCT to highlight target areas for potential new treatments.
Keywords	Cell Growth & Division ; Genitourinary Cancers ; Medical Genetics ; Medicine ; R ; Science ; Q
Subject code	610
Language	English
Publishing date	2013-02-01T00:00:00Z
Publisher	F1000 Research Ltd
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: A unique combination of male germ cell miRNAs coordinates gonocyte differentiation.

McIver, Skye C / Stanger, Simone J / Santarelli, Danielle M / Roman, Shaun D / Nixon, Brett / McLaughlin, Eileen A

PloS one

2012 Volume 7, Issue 4, Page(s) e35553

Abstract: The last 100 years have seen a concerning decline in male reproductive health associated with decreased sperm production, sperm function and male fertility. Concomitantly, the incidence of defects in reproductive development, such as undescended testes, ... ...

Abstract	The last 100 years have seen a concerning decline in male reproductive health associated with decreased sperm production, sperm function and male fertility. Concomitantly, the incidence of defects in reproductive development, such as undescended testes, hypospadias and testicular cancer has increased. Indeed testicular cancer is now recognised as the most common malignancy in young men. Such cancers develop from the pre-invasive lesion Carcinoma in Situ (CIS), a dysfunctional precursor germ cell or gonocyte which has failed to successfully differentiate into a spermatogonium. It is therefore essential to understand the cellular transition from gonocytes to spermatogonia, in order to gain a better understanding of the aetiology of testicular germ cell tumours. MicroRNA (miRNA) are important regulators of gene expression in differentiation and development and thus highly likely to play a role in the differentiation of gonocytes. In this study we have examined the miRNA profiles of highly enriched populations of gonocytes and spermatogonia, using microarray technology. We identified seven differentially expressed miRNAs between gonocytes and spermatogonia (down-regulated: miR-293, 291a-5p, 290-5p and 294, up-regulated: miR-136, 743a and 463). Target prediction software identified many potential targets of several differentially expressed miRNA implicated in germ cell development, including members of the PTEN, and Wnt signalling pathways. These targets converge on the key downstream cell cycle regulator Cyclin D1, indicating that a unique combination of male germ cell miRNAs coordinate the differentiation and maintenance of pluripotency in germ cells.
MeSH term(s)	Animals ; Cyclin D1/metabolism ; Gene Expression Profiling ; Gene Expression Regulation ; Germ Cells/metabolism ; Germ Cells/physiology ; Male ; Mice ; MicroRNAs/genetics ; MicroRNAs/metabolism ; Oligonucleotide Array Sequence Analysis ; PTEN Phosphohydrolase/metabolism ; Real-Time Polymerase Chain Reaction ; Spermatogenesis/genetics ; Spermatogonia/metabolism ; Spermatogonia/physiology ; Wnt Signaling Pathway
Chemical Substances	Ccnd1 protein, mouse ; MicroRNAs ; Cyclin D1 (136601-57-5) ; PTEN Phosphohydrolase (EC 3.1.3.67) ; Pten protein, mouse (EC 3.1.3.67)
Language	English
Publishing date	2012-04-20
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	1932-6203
ISSN (online)	1932-6203
DOI	10.1371/journal.pone.0035553
Database	MEDical Literature Analysis and Retrieval System OnLINE

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