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

Development ◽  
1999 ◽  
Vol 126 (10) ◽  
pp. 2215-2225 ◽  
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.

scholarly journals Single-cell transcriptomics reveals immune response of intestinal cell types to viral infection

2020 ◽  
Author(s):  
Sergio Triana ◽  
Megan L. Stanifer ◽  
Mohammed Shahraz ◽  
Markus Mukenhirn ◽  
Carmon Kee ◽  
...  
Keyword(s):  
Immune Response ◽  
Single Cell ◽  
Cell Lineage ◽  
Enteric Virus ◽  
Cell Types ◽  
Intestinal Cell ◽  
Intestinal Epithelial ◽  
Proliferating Cells ◽  
Interferon Stimulated Genes ◽  
Human Intestinal Epithelium

AbstractHuman intestinal epithelial cells form a primary barrier protecting us from pathogens, yet only limited knowledge is available about individual contribution of each cell type to mounting an immune response against infection. Here, we developed a pipeline combining single-cell RNA-Seq and highly-multiplex RNA imaging and applied it to human intestinal organoids infected with human astrovirus, a model human enteric virus. We found that interferon controls the infection and that astrovirus infects all major cell types and lineages with a preferential infection of proliferating cells. Intriguingly, each intestinal epithelial cell lineage has a unique basal expression of interferon-stimulated genes and, upon astrovirus infection, undergoes an antiviral transcriptional reprogramming by upregulating distinct sets of interferon-stimulated genes. These findings suggest that in the human intestinal epithelium, each cell lineage plays a unique role in resolving virus infection. Our pipeline can be applicable to other organoids and viruses, opening new avenues to unravel roles of individual cell types in viral pathogenesis.

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

2010 ◽  
Vol 17 (1) ◽  
pp. 283-291 ◽  
Author(s):  
Yu-cheng Wang ◽  
Marlene B Zuraek ◽  
Yasuhiro Kosaka ◽  
Yasuharu Ota ◽  
Michael S German ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Small Intestine ◽  
Cell Lineage ◽  
Lineage Tracing ◽  
Serotonin Neurons ◽  
In The Wild ◽  
Normal Human ◽  
Node Metastases ◽  
Novel Target

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.

scholarly journals Requirements for cDC2 positioning in blood-exposed regions of the neonatal and adult spleen

2020 ◽  
Vol 217 (11) ◽  
Author(s):  
Dan Liu ◽  
Jiaxi Wu ◽  
Jinping An ◽  
Jason G. Cyster
Keyword(s):  
B Cells ◽  
Immune Responses ◽  
B Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Cell Types ◽  
White Pulp ◽  
Neonatal Mice ◽  
Adult Mice ◽  
Multiple Cell

The marginal zone (MZ) of the spleen contains multiple cell types that are involved in mounting rapid immune responses against blood-borne pathogens, including conventional dendritic cells (cDCs) and MZ B cells. MZ B cells develop later than other B cell types and are sparse in neonatal mice. Here, we show that cDC2s are abundant in the MZ of neonatal compared with adult mice. We find that conditions associated with reduced MZ B cell numbers in adult mice cause increased cDC2 occupancy of the MZ. Treatment with the S1PR1-modulating drug, FTY720, causes cDC2 movement into the MZ through the indirect mechanism of displacing MZ B cells into follicles. Splenic cDC2s express high amounts of α4β1 and αLβ2 integrins and depend on these integrins and the adaptor Talin for their retention in blood-exposed regions of the spleen. Splenic CD4 T cell activation by particulate antigens is increased in mice with higher cDC2 density in the MZ, including in neonatal mice. Our work establishes requirements for homeostatic cDC2 positioning in the spleen and provides evidence that localization in blood-exposed regions around the white pulp augments cDC2 capture of particulate antigens. We suggest that MZ positioning of cDC2s partially compensates for the lack of MZ B cells during the neonatal period.

scholarly journals Protein Tyrosine Kinase 6 Negatively Regulates Growth and Promotes Enterocyte Differentiation in the Small Intestine

2006 ◽  
Vol 26 (13) ◽  
pp. 4949-4957 ◽  
Author(s):  
Andrea Haegebarth ◽  
Wenjun Bie ◽  
Ruyan Yang ◽  
Susan E. Crawford ◽  
Valeri Vasioukhin ◽  
...  
Keyword(s):  
Small Intestine ◽  
Epithelial Cells ◽  
Tyrosine Kinase ◽  
Protein Tyrosine Kinase ◽  
Cell Types ◽  
Intestinal Epithelial ◽  
Fatty Acid Binding ◽  
Protein Tyrosine ◽  
Adult Mice ◽  
Enterocyte Differentiation

ABSTRACT Protein tyrosine kinase 6 (PTK6) (also called Brk or Sik) is an intracellular tyrosine kinase that is expressed in breast cancer and normal epithelial linings. In adult mice, PTK6 expression is high in villus epithelial cells of the small intestine. To explore functions of PTK6, we disrupted the mouse Ptk6 gene. We detected longer villi, an expanded zone of PCNA expression, and increased bromodeoxyuridine incorporation in the PTK6-deficient small intestine. Although differentiation of major epithelial cell types occurred, there was a marked delay in expression of intestinal fatty acid binding protein, suggesting a role for PTK6 in enterocyte differentiation. However, fat absorption was comparable in wild-type and Ptk6 −/− mice. It was previously shown that the serine threonine kinase Akt is a substrate of PTK6 and that PTK6-mediated phosphorylation of Akt on tyrosine resulted in inhibition of Akt activity. Consistent with these findings, we detected increased Akt activity and nuclear β-catenin in intestines of PTK6-deficient mice and decreased nuclear localization of the Akt substrate FoxO1 in villus epithelial cells. PTK6 contributes to maintenance of tissue homeostasis through negative regulation of Akt in the small intestine and is associated with cell cycle exit and differentiation in normal intestinal epithelial cells.

Cell lineages in the embryonic kidney: their inductive interactions and signalling molecules

1998 ◽  
Vol 76 (6) ◽  
pp. 1009-1016 ◽  
Author(s):  
Hannu Sariola ◽  
Kirsi Sainio
Keyword(s):  
Growth Factor ◽  
Cell Lineage ◽  
Cell Types ◽  
Molecular Data ◽  
Ureteric Bud ◽  
Signalling Molecules ◽  
Developmental Sequences ◽  
Signalling Molecule ◽  
Organ Specific ◽  
Bud Initiation

The first signalling genes acting in the inductive interactions in the kidney have now been identified. Differentiation of the permanent kidney or the metanephros is critically dependent on inductive signalling between the nephrogenic mesenchyme and ureteric bud epithelium. Further inductive interactions occur between developing nephrons, interstitial stroma, endothelial cells and neurones. Glial-cell-line-derived neurotrophic factor is a signal for the ureteric bud initiation and branching, and Wnt4 is an autocrine epithelializing signal at the pretubular stage of nephron formation. The signals for renal angiogenesis and innervation are less well defined, but seem to include vascular endothelial growth factor and neurotrophins, at least. The ureteric-bud-derived signal for induction of the nephrogenic mesenchyme (to bring the cells to the condensate stage) is not yet known, but fibroblast growth factor 2 is a good candidate. None of the signalling genes identified from the embryonic kidney is specific to the organ, which raises some general questions. How do the organs develop from similar rudiments to various patterns with different cell types and functions? Does the information for organ-specific differentiation pathways retain in the epithelial or mesenchymal compartment? The present, rather fragmentary molecular data would favour the view that similar molecules acting in different combinations and developmental sequences, rather than few organ-specific master genes, could be responsible for the divergence of patterning.Key words: inductive tissue interaction, metanephros, apoptosis, signalling molecule, cell lineage, morphogenesis.

scholarly journals c-Myc Is Required for the Formation of Intestinal Crypts but Dispensable for Homeostasis of the Adult Intestinal Epithelium

2005 ◽  
Vol 25 (17) ◽  
pp. 7868-7878 ◽  
Author(s):  
Michael D. Bettess ◽  
Nicole Dubois ◽  
Mark J. Murphy ◽  
Christelle Dubey ◽  
Catherine Roger ◽  
...  
Keyword(s):  
Small Intestine ◽  
Intestinal Epithelium ◽  
Cell Types ◽  
Molecular Evidence ◽  
Normal Numbers ◽  
Normal Epithelium ◽  
Independent Manner ◽  
Adult Mice ◽  
Canonical Wnt

ABSTRACT In self-renewing tissues such as the skin epidermis and the bone marrow, Myc proteins control differentiation of stem cells and proliferation of progenitor cell types. In the epithelium of the small intestine, we show that c-Myc and N-Myc are expressed in a differential manner. Whereas c-Myc is expressed in the proliferating transient-amplifying compartment of the crypts, N-Myc is restricted to the differentiated villus epithelium and a single cell located near the crypt base. c-Myc has been implicated as a critical target of the canonical Wnt pathway, which is essential for formation and maintenance of the intestinal mucosa. To genetically assess the role of c-Myc during development and homeostasis of the mammalian intestine we induced deletion of the c-myc flox allele in the villi and intestinal stem cell-bearing crypts of juvenile and adult mice, via tamoxifen-induced activation of the CreERT2 recombinase, driven by the villin promoter. Absence of c-Myc activity in the juvenile mucosa at the onset of crypt morphogenesis leads to a failure to form normal numbers of crypts in the small intestine. However, all mice recover from this insult to form and maintain a normal epithelium in the absence of c-Myc activity and without apparent compensation by N-Myc or L-Myc. This study provides genetic and molecular evidence that proliferation and expansion of progenitors necessary to maintain the adult intestinal epithelium can unexpectedly occur in a Myc-independent manner.

scholarly journals BMP signalling is critical for maintaining homeostasis of hair follicles and intestine in adult mice

2017 ◽  
Author(s):  
Aditi Nag ◽  
Pallavi Nigam ◽  
Abhishek L. Narayanan ◽  
Megha Kumar ◽  
Ritika Ghosal ◽  
...  
Keyword(s):  
Cell Types ◽  
Hair Follicles ◽  
Intestinal Cell ◽  
Knock Out ◽  
Adult Mice ◽  
Rapid Changes ◽  
Anagen Hair ◽  
Mouse Intestine ◽  
Bmp Signalling

AbstractBMP signalling play critical roles during embryonic development, however, its roles have not been extensively studied in the maintenance of adult tissue homeostasis. In this study we have used temporal knock out of Bmp2 and Bmp4 to uncover the role of BMP signalling in adult mice. We observed rapid changes in the adult hair follicles and the intestine within two days of depleting BMP signalling, which demonstrates the critical and acute requirement of BMP signalling in maintaining homeostasis in these tissues. In addition, our study demonstrates that while BMP signalling is required for maintenance of quiescence in telogen hair follicles, it is needed for survival and proliferation in late anagen hair follicles. Our study also reveals differential requirement of BMP signalling in differentiation of distinct intestinal cell types. In addition, Loss of BMP signalling rapidly promotes early neoplastic transformations in mouse intestine.

scholarly journals Hypothalamic and pituitary development: novel insights into the aetiology

2007 ◽  
Vol 157 (suppl_1) ◽  
pp. S3-S14 ◽  
Author(s):  
Daniel Kelberman ◽  
Mehul Tulsidas Dattani
Keyword(s):  
Transcription Factor ◽  
Transcription Factors ◽  
Cell Types ◽  
Hormone Deficiency ◽  
Pituitary Hormone ◽  
Gene Encoding ◽  
Complex Disorders ◽  
Signalling Molecules ◽  
Pituitary Development ◽  
Transgenic Murine Models

The anterior pituitary gland is a central regulator of growth, reproduction and homeostasis, and is the end-product of a carefully orchestrated pattern of expression of signalling molecules and transcription factors leading to the development of this complex organ secreting six hormones from five different cell types. Naturally occurring and transgenic murine models have demonstrated a role for many of these molecules in the aetiology of combined pituitary hormone deficiency (CPHD). These include the transcription factors HESX1, PROP1, POU1F1, LHX3, LHX4, TBX19, SOX2 and SOX3. The expression pattern of these transcription factors dictates the phenotype that results when the gene encoding the relevant transcription factor is mutated. The highly variable phenotype may consist of isolated hypopituitarism, or more complex disorders such as septo-optic dysplasia and holoprosencephaly. Since mutations in any one transcription factor are uncommon, and since the overall incidence of mutations in known transcription factors is low in patients with CPHD, it is clear that many genes remain to be identified, and the characterization of these will further elucidate the pathogenesis of these complex conditions and also shed light on normal pituitary development.

scholarly journals Expression of the Runt domain-encoding PEBP2 alpha genes in T cells during thymic development.

1995 ◽  
Vol 15 (3) ◽  
pp. 1662-1670 ◽  
Author(s):  
M Satake ◽  
S Nomura ◽  
Y Yamaguchi-Iwai ◽  
Y Takahama ◽  
Y Hashimoto ◽  
...  
Keyword(s):  
T Cells ◽  
Transcription Factor ◽  
T Cell ◽  
Bone Marrow Cells ◽  
Cell Lineage ◽  
Runt Domain ◽  
Newborn Mice ◽  
Thymic Development ◽  
Adult Mice ◽  
Mouse Tissues

The PEBP2 alpha A and PEBP2 alpha B genes encode the DNA-binding subunit of a murine transcription factor, PEBP2, which is implicated as a T-cell-specific transcriptional regulator. These two related genes share the evolutionarily conserved region encoding the Runt domain. PEBP2 alpha B is the murine counterpart of human AML1, which is located at the breakpoints of the 8;21 and 3;21 chromosome translocations associated with acute myeloid leukemia. Northern (RNA) blots of various adult mouse tissues revealed that the levels of expression of both genes were most prominent in the thymus. Furthermore, transcripts of PEBP2 alpha A and mouse AML1/PEBP2 alpha B were detected in T lymphocytes in the thymuses from day 16 embryos and newborns, as well as 4-week-old adult mice, by in situ hybridization. The expression of the genes persisted in peripheral lymph nodes of adult mice. The transcripts were detected in all the CD4- CD8-, CD4+ CD8+, CD4+ CD8-, and CD4- CD8+ cell populations. The results indicated that both genes are expressed in T cells throughout their development, supporting the notion that PEBP2 is a T-cell-specific transcription factor. Transcripts of mouse AML1/PEBP2 alpha B were also detected in day 12 fetal hematopoietic liver and in the bone marrow cells of newborn mice. The implication of mouse AML1/PEBP2 alpha B expression in hematopoietic cells other than those of T-cell lineage is discussed in relation to myeloid leukemogenesis.

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