dlk Inhibits Stem Cell Factor‐Induced Colony Formation of Murine Hematopoietic Progenitors: Hes‐1‐Independent Effect

Ohno, Noriko; Izawa, Akiko; Hattori, Masao; Kageyama, Ryoichiro; Sudo, Tetsuo

doi:10.1634/stemcells.19-1-71

Cited by 68 publications

(52 citation statements)

References 57 publications

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“…Both positive 17 and negative 41 effects of environmental Dlk1 on HSPCs have been described, which are likely to be dependent on the specific cellular context. The presence of physiologically important negative regulators of HSCs in the adult bone marrow niche has already been described, [42][43][44] and although no negative regulators have been identified in the AGM, it is known that HSC numbers are limited here.…”

Section: Discussionmentioning

confidence: 99%

Dlk1 is a negative regulator of emerging hematopoietic stem and progenitor cells

Mirshekar-Syahkal

Haak²,

Kimber

et al. 2012

Haematologica

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The first mouse adult-repopulating hematopoietic stem cells emerge in the aorta-gonad-mesonephros region at embryonic day (E) 10.5. Their numbers in this region increase thereafter and begin to decline at E12.5, thus pointing to the possible existence of both positive and negative regulators of emerging hematopoietic stem cells. Our recent expression analysis of the aorta-gonad-mesonephros region showed that the Delta-like homologue 1 (Dlk1) gene is up-regulated in the region of the aorta-gonad-mesonephros where hematopoietic stem cells are preferentially located. To analyze its function, we studied Dlk1 expression in wild-type and hematopoietic stem cell-deficient embryos and determined hematopoietic stem and progenitor cell activity in Dlk1 knockout and overexpressing mice. Its role in hematopoietic support was studied in co-culture experiments using stromal cell lines that express varying levels of Dlk1. We show here that Dlk1 is expressed in the smooth muscle layer of the dorsal aorta and the ventral sub-aortic mesenchyme, where its expression is dependent on the hematopoietic transcription factor Runx1. We further demonstrate that Dlk1 has a negative impact on hematopoietic stem and progenitor cell activity in the aorta-gonad-mesonephros region in vivo, which is recapitulated in co-cultures of hematopoietic stem cells on stromal cells that express varying levels of Dlk1. This negative effect of Dlk1 on hematopoietic stem and progenitor cell activity requires the membrane-bound form of the protein and cannot be recapitulated by soluble Dlk1. Together, these data suggest that Dlk1 expression by cells of the aorta-gonad-mesonephros hematopoietic microenvironment limits hematopoietic stem cell expansion and is, to our knowledge, the first description of such a negative regulator in this tissue.

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Section: Discussionmentioning

confidence: 99%

Dlk1 is a negative regulator of emerging hematopoietic stem and progenitor cells

Mirshekar-Syahkal

Haak²,

Kimber

et al. 2012

Haematologica

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“…Previous studies have shown that Dlk1 functions as a dimer, although the dimerization domain has yet to be mapped [12,45]. It is possible that the juxtamembrane region functions as a protein dimerization domain whereby Dlk1 is able to homodimerize with itself or form a heterodimer with a yet to be identified signaling partner, and the resulting dimer transduces Dlk1-mediated signaling.…”

Section: Discussionmentioning

confidence: 99%

Regulation of growth hormone expression by Delta-like protein 1 (Dlk1)

Ansell

Zhou

Schjeide

et al. 2007

Molecular and Cellular Endocrinology

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Delta-like protein 1 (Dlk1) is a transmembrane protein characterized by epidermal growth factor (EGF)-like repeats. Dlk1, which is also known as preadipocyte factor 1 (pref-1) because of its ability to inhibit preadipocyte differentiation, regulates the differentiation of several other cell types through unknown mechanisms. To elucidate Dlk1 functions, identification of Dlk1-regulated target genes is critical. The observation that Dlk1 is expressed in many endocrine tissues suggests that Dlk1 may have endocrine-related functions. Because Dlk1 is expressed in GH producing cells, we hypothesize that one function of Dlk1 is to regulate GH expression. We found that GH mRNA, protein, and secretion were significantly decreased in GH3 pituitary cell clones that stably express Dlk1. In contrast, Dlk1 expression was unable to alter prolactin expression. Co-transfection of GH3 cells with a GH promoter-regulated reporter gene showed that Dlk1 repressed GH promoter activity. Deletion and mutation analysis of the GH promoter indicated that Pit-1 binding sites in the GH promoter are required for Dlk1-mediated repression. Furthermore, Dlk1 expression represses Pit-1-mediated transcription when both proteins are co-expressed in MCF-7 cells. Deletion analysis of Dlk1 revealed that the ability of Dlk1 to regulate GH promoter activity is independent of both its EGF-like repeats and its ability to modulate MAP kinase activity. The observation that Dlk1 regulates GH expression identifies the first endocrine function of Dlk1, establishes GH as a Dlk1-regulated target gene, and provides a model system to facilitate studies of Dlk1-mediated signaling.

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“…47,48 Dlk1 inhibits stem cell factor-induced colony formation in murine hematopoietic progenitors in a HES-independent way. 49 However there are also indications that Dlk1 is a valid partner of the Delta-Notch pathway. The stimulatory effect of Dlk1 on the cellularity of thymocytes was shown to be mediated by increased HES1 expression.…”

Section: Discussionmentioning

confidence: 99%

High delta‐like 1 expression in a subset of neuroblastoma cell lines corresponds to a differentiated chromaffin cell type

Limpt

Chan

Sluis

et al. 2003

Intl Journal of Cancer

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dlk Inhibits Stem Cell Factor‐Induced Colony Formation of Murine Hematopoietic Progenitors: Hes‐1‐Independent Effect

Cited by 68 publications

References 57 publications

Dlk1 is a negative regulator of emerging hematopoietic stem and progenitor cells

Dlk1 is a negative regulator of emerging hematopoietic stem and progenitor cells

Regulation of growth hormone expression by Delta-like protein 1 (Dlk1)

High delta‐like 1 expression in a subset of neuroblastoma cell lines corresponds to a differentiated chromaffin cell type

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