The ETS oncogene family transcription factor FEV identifies serotonin-producing cells in normal and neoplastic small intestine

Neuroendocrine (NE) or carcinoid tumors of the small intestine (SI) frequently metastasize and produce the hormone serotonin, causing significant morbidity and mortality. A member of the ETS oncogene family of transcription factors, Fev, acts with the homeodomain transcription factor Nkx2.2 in the development of serotonin neurons in mice. In this study, we investigated the role of Fev in normal and neoplastic SI. In NE tumors (NETs) of the SI, serotonin stimulates tumor growth and causes debilitating symptoms, such as diarrhea, flushing, wheezing, and right-sided valvular heart disease (i.e. carcinoid syndrome). Compared with those in the matched normal human SI, FEV expression levels were significantly elevated in primary NETs (20-fold, P<0.0001), lymph node metastases (35-fold, P=0.004), and NET liver metastases (22-fold, P<0.0001) resected from patients with serotonin excess. Fev is expressed in the wild type but not in Nkx2.2 (−/−) mouse SI, in which cells producing serotonin are absent. Using recombination-based cell lineage tracing, we found that FEV-positive cells give rise to serotonin-producing cells in the SI. In Fev (−/−) mouse SI, we observed no difference in the number of cells producing serotonin or other hormones. We conclude that FEV expression identifies serotonin-producing cells in normal and neoplastic SI and is a novel target for diagnosis of patients with NETs of the SI.

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Targeted disruption of the homeobox transcription factor Nkx2-3 in mice results in postnatal lethality and abnormal development of small intestine and spleen

Development ◽

10.1242/dev.126.10.2215 ◽

1999 ◽

Vol 126 (10) ◽

pp. 2215-2225 ◽

Cited By ~ 3

Author(s):

O. Pabst ◽

R. Zweigerdt ◽

H.H. Arnold

Keyword(s):

Transcription Factor ◽

Small Intestine ◽

Cell Lineage ◽

Cell Types ◽

Abnormal Development ◽

Intestinal Cell ◽

White Pulp ◽

Morphological Alterations ◽

Signalling Molecules ◽

Adult Mice

The homeodomain transcription factor Nkx2-3 is expressed in gut mesenchyme and spleen of embryonic and adult mice. Targeted inactivation of the Nkx2-3 gene results in severe morphological alterations of both organs and early postnatal lethality in the majority of homozygous mutants. Villus formation in the small intestine appears considerably delayed in Nkx2-3(−)/- foetuses due to reduced proliferation of the epithelium, while massively increased growth of crypt cells ensues in surviving adult mutants. Interestingly, differentiated cell types of the intestinal epithelium are present in homozygous mutants, suggesting that Nkx2-3 is not required for their cell lineage allocation or migration-dependent differentiation. Hyperproliferation of the gut epithelium in adult mutants is associated with markedly reduced expression of BMP-2 and BMP-4, suggesting that these signalling molecules may be involved in mediating non-cell-autonomous control of intestinal cell growth. Spleens of Nkx2-3 mutants are generally smaller and contain drastically reduced numbers of lymphatic cells. The white pulp appears anatomically disorganized, possibly owing to a homing defect in the spleen parenchyme. Moreover, some of the Nkx2-3 mutants exhibit asplenia. Taken together these observations indicate that Nkx2-3 is essential for normal development and functions of the small intestine and spleen.

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The Mad1 transcription factor is a novel target of activin and TGF-β action in keratinocytes: possible role of Mad1 in wound repair and psoriasis

Oncogene ◽

10.1038/sj.onc.1204937 ◽

2001 ◽

Vol 20 (51) ◽

pp. 7494-7504 ◽

Cited By ~ 35

Author(s):

Silke Werner ◽

Hans-Dietmar Beer ◽

Cornelia Mauch ◽

Bernhard Lüscher ◽

Sabine Werner

Keyword(s):

Transcription Factor ◽

Wound Repair ◽

Novel Target

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Nuclear expression of the non–B-cell lineage Sox11 transcription factor identifies mantle cell lymphoma

Blood ◽

10.1182/blood-2007-06-093401 ◽

2008 ◽

Vol 111 (2) ◽

pp. 800-805 ◽

Cited By ~ 128

Author(s):

Sara Ek ◽

Michael Dictor ◽

Mats Jerkeman ◽

Karin Jirström ◽

Carl A. K. Borrebaeck

Keyword(s):

Transcription Factor ◽

Cyclin D1 ◽

Mantle Cell Lymphoma ◽

Nuclear Protein ◽

Cell Lymphoma ◽

Cell Lineage ◽

B Lymphopoiesis ◽

Mantle Cell ◽

Appropriate Therapy

Mantle cell lymphoma (MCL) is defined pathologically by the detection of CD20, CD5, and most importantly cyclin D1 (CCND1). Its distinction from other lymphomas is important for prognosis and appropriate therapy, but occasional cases may fail to express CCND1 and morphologic simulators may express CD20 and CD5 but not CD23. In this study, we show that the transcription factor Sox11 is specifically expressed in the nucleus of MCL compared with other lymphomas and benign lymphoid tissue. Although the role of Sox11 presently is not known in lymphocyte ontogeny, it is normally expressed in the developing central nervous system in the embryo and shows sequence homology with Sox4, a transcription factor crucial for B lymphopoiesis. Sox11 mRNA is increased in gliomas compared with healthy brain tissue, suggesting a role in malignant transformation and/or cell survival. Our novel finding of specific overexpression of Sox11 mRNA and nuclear protein in both cyclin D1–positive and – negative MCL may be useful for the diagnosis of MCL as a complement to cyclin D1 and also suggests a functional role for Sox11 in MCL.

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Cell autonomous TGF-beta signaling is essential for cell recruitment into degenerating tendons

10.1101/2020.11.11.378505 ◽

2020 ◽

Author(s):

Guak-Kim Tan ◽

Brian A. Pryce ◽

Anna Stabio ◽

Douglas R. Keene ◽

Sara F. Tufa ◽

...

Keyword(s):

Gene Deletion ◽

Critical Role ◽

Cell Lineage ◽

Lineage Tracing ◽

Type Ii ◽

Tgfβ Signaling ◽

Targeted Disruption ◽

Cell Recruitment ◽

Inducible Gene

AbstractUnderstanding the role of cell recruitment in tendon disorders is critical for improvements in regenerative therapy. We recently reported that targeted disruption of TGFβ type II receptor in the tendon cell lineage (Tgfbr2ScxCre) resulted in tenocyte dedifferentiation and tendon degradation in post-natal stages. Here we extend the analysis and identify direct recruitment of stem/progenitor cells into the degenerative mutant tendons. Cre-lineage tracing indicates that these cells are not derived from tendon ensheathing tissues or from a Scleraxis-lineage, and they turned on tendon markers only upon entering the mutant tendons. Through immunohistochemistry and inducible gene deletion, we further find that the recruited cells originated from a Sox9-expressing lineage and their recruitment was dependent on cell-autonomous TGFβ signaling. These results thus differ from previous reports of cell recruitment into injured tendons, and suggest a critical role for TGFβ signaling and cell recruitment in the etiology and treatment of tendon degeneration.

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Reassessing embryogenesis in the Ctenophora: the inductive role of e1 micromeres in organizing ctene row formation in the ‘mosaic’ embryo, Mnemiopsis leidyi

Development ◽

10.1242/dev.124.10.1999 ◽

1997 ◽

Vol 124 (10) ◽

pp. 1999-2006

Author(s):

M.Q. Martindale ◽

J.Q. Henry

Keyword(s):

Cell Lineage ◽

Lineage Tracing ◽

Mnemiopsis Leidyi ◽

Adjacent Cell ◽

Embryonic Patterning ◽

Marine Animals ◽

Cell Stage ◽

Locomotory Behavior ◽

Mosaic Embryo

Ctenophores are a phylum of diploblastic marine animals displaying biradial symmetry organized along an oral-aboral axis. One of the apomorphic sets of adult structures in ctenophores are the eight external comb rows, which run along the oral-aboral axis. Comb rows consist of serial arrays of individual comb plates of cilia, which beat in a coordinated fashion for locomotory behavior. Classical cell lineage experiments using chalk particles indicated that comb rows are derived exclusively from the four e1 micromeres at the 16-cell stage. This conclusion was also supported by the fact that no ctene rows (or their underlying endodermal canals) form when all four e1 micromeres were deleted. We have used intracellular diI cell lineage tracing to determine that, in addition to e1 micromeres, the four m1 micromeres also make significant contributions to the ctene rows. Thus, e1 micromere derivatives not only generate comb plates but are required for ctene row formation by m1 derivatives. These results demonstrate that inductive interactions are an important component of early development in ctenophores and indicate that e1 micromeres influence the development of adjacent cell lineages (both m1 and endodermal lineages) during ctenophore embryogenesis. In addition, intracellular labeling has revealed that there are subtle variations in the composition of clones derived from identified embryonic blastomeres. Together these findings reveal a picture of ctenophore embryogenesis, which is in marked contrast to the former rigid ‘mosaic’ reputation of ctenophore development, and invite speculation as to the role of the cleavage program in embryonic patterning in the lower Metazoa.

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Piecemeal regulation of convergent neuronal lineages by bHLH transcription factors in C. elegans

10.1101/2021.03.31.437939 ◽

2021 ◽

Author(s):

Neda Masoudi ◽

Ralf Schnabel ◽

Oliver Hobert

Keyword(s):

Transcription Factor ◽

Transcription Factors ◽

Cell Lineage ◽

Contralateral Side ◽

Mirror Image ◽

Lineage Tracing ◽

Bhlh Transcription Factor ◽

C Elegans ◽

Distinct Lineage ◽

Identity Transformations

Classic cell lineage studies in the nematode Caenorhabditis elegans as well as recent lineage tracing in vertebrates have shown that cells of the same type can be generated by distinct cellular lineages that originate in different parts of the developing embryo ('lineage convergence'). Several C. elegans neuron classes composed of left/right or radially symmetric class members display such lineage convergence, in that individual neurons of the same class derive from distinct, non-bilaterally symmetric lineages. We show here that the C. elegans Atonal homolog lin-32/Ato, a bHLH transcription factor, is differentially expressed in neuronal lineages that give rise to left/right or radially symmetric class members. Loss of lin-32/Ato results in the selective loss of the expression of panneuronal markers and terminal selector-type transcription factors that confer neuron class-specific features. We discovered that another bHLH transcription factor, the Achaete Scute-homolog hlh-14 is expressed in mirror image pattern to lin-32/Ato in a subset of the left/right symmetric neuron pairs and is required to induce neuronal identity and terminal selector expression on the contralateral side of the animal. These findings demonstrate that distinct lineage histories converge via distinct bHLH factors on the level of induction of terminal selector identity determinants, which thus serve as integrators of distinct lineage histories. We also describe neuron-to-neuron identity transformations in lin-32/Ato mutants, which we propose to also be the result of misregulation of terminal selector gene expression.

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