WHIM syndrome–linked CXCR4 mutations impair lymphoid progenitor specification in mice
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1130487 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR29666712_1.fastq.gz | Fastqsanger.gz | |||
| SRR29666712_2.fastq.gz | Fastqsanger.gz | |||
| SRR29666713_1.fastq.gz | Fastqsanger.gz | |||
| SRR29666713_2.fastq.gz | Fastqsanger.gz | |||
| SRR29666714_1.fastq.gz | Fastqsanger.gz |
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Project description:Both cell-intrinsic cues and niche-derived cell-extrinsic cues drive lineage the specification of hematopoietic multipotent progenitors (MPPs) in the bone marrow, comprising multipotent MPP1 cells and lineage-restricted MMP2, MPP3, and MPP4 cells. WHIM syndrome is a rare congenital immunodeficiency caused by gain-of-function mutations in the gene encoding the chemokine receptor CXCR4 and characterized by an increase in the number of myeloid cells that are produced in but fail to exit from the bone marrow. Here, we found that CXCR4 signaling regulated the localization and fate of MPPs. Knock-in mice bearing a WHIM syndrome–associated CXCR4 mutation phenocopied the myeloid-skewing of bone marrow in patients. Myeloid rewiring of lymphoid-primed MPPs (MPP4s) in the mice was associated with enhanced mechanistic target of rapamycin (mTOR) signaling and overactive Oxphos metabolism. The fate of these MPP4 cells was also affected by molecular changes established at the MPP1 level. Mutant MPP4 displayed altered localization in the bone marrow relative to perivascular structures, suggesting that extrinsic cues also contribute to their myeloid skewing. Chronic treatment with the CXCR4 antagonist AMD3100 or the mTOR inhibitor Rapamycin rescued the lymphoid capacities of mutant progenitors including MPP4, demonstrating a pivotal role for the CXCR4-mTOR axis in regulating MPP4 fate. Our study thus provides mechanistic insights into how CXCR4 signaling regulates the lymphoid potential of MPPs.
2025-01-22 | GSE271225 | GEO
Project description:Primary immunodeficiency diseases (PIDDs) encompass a range of congenital disorders that adversely influence both innate and adaptive immune systems. While individuals diagnosed with PIDDs often exhibit elevated levels of emotional distress and neuropsychological challenges - such as depression and anxiety - the neurobiological underpinnings linking genetic alterations in PIDDs to their neurological manifestations have not been so far explored. Here, by mapping the expression of PIDD genes in transcriptional datasets sampling the human brain across multiple areas and ages, we identified a notable regional enrichment in the cerebellum, which encompasses neuronal and glial subtypes, extending beyond the immune cells. Aiming at elucidating the impact of PIDD genetic alterations on brain development, we focus on WHIM syndrome, caused by CXCR4 mutations. Consistently with clinical reports on WHIM patients, magnetic resonance imaging and histological analysis performed on WHIM mouse model showed distinct cerebellar foliation deficits associated with mild motor impairment and anxiety-like behavior from early development. Despite the restricted expression of CXCR4 in rhombic lip-derived progenitors, single-cell profiling uncovered a pervasive transcriptional alteration across various cerebellar cell types, well beyond the cell-autonomous effects of the mutation on the granule lineage. Significant downregulation of genes involved in dendrite branching and axonal elongation molecularly defined the reduced arborization observed in WHIM Purkinje cells, which is associated with altered lobule-specific frequency patterns by high-density multielectrode array recordings. In utero intraventricular administration of CXCR4 antagonist AMD3100 - currently in clinical trials in patients - successfully rescued both morphological and behavioral defects. This unravels a direct effect of the WHIM-associated Cxcr4-Cxcl12 axis on compromised cerebellar assembly of motor and anxiety-associated circuits. Our findings underscore the contribution of the cerebellum to emotional distress while emphasizing the importance of considering neurological implications in the management of PIDDs.
2025-06-06 | GSE266671 | GEO
Project description:This study provides gene expression profiles of spleen and peripheral lymph node stromal cell subsets from a CXCR4 gain-of- function mouse model of WHIM syndrome at the population level.
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Project description:Collombet2016 - Lymphoid and myeloid cell
specification and transdifferentiation
This model is described in the article:
Logical modeling of lymphoid
and myeloid cell specification and transdifferentiation
Samuel Collombet, Chris van Oevelen,
Jose Luis Sardina Ortega, Wassim Abou-Jaoudé, Bruno Di
Stefano, Morgane Thomas-Chollier, Thomas Graf, and Denis
Thieffry
Proceedings of the National Academy of
Sciences of the United States of America
Abstract:
Blood cells are derived from a common set of hematopoietic
stem cells, which differentiate into more specific progenitors
of the myeloid and lymphoid lineages, ultimately leading to
differentiated cells. This developmental process is controlled
by a complex regulatory network involving cytokines and their
receptors, transcription factors, and chromatin remodelers.
Using public data and data from our own molecular genetic
experiments (quantitative PCR, Western blot, EMSA) or
genome-wide assays (RNA-sequencing, ChIP-sequencing), we have
assembled a comprehensive regulatory network encompassing the
main transcription factors and signaling components involved in
myeloid and lymphoid development. Focusing on B-cell and
macrophage development, we defined a qualitative dynamical
model recapitulating cytokine-induced differentiation of common
progenitors, the effect of various reported gene knockdowns,
and the reprogramming of pre-B cells into macrophages induced
by the ectopic expression of specific transcription factors.
The resulting network model can be used as a template for the
integration of new hematopoietic differentiation and
transdifferentiation data to foster our understanding of
lymphoid/myeloid cell-fate decisions.
This model is hosted on
BioModels Database
and identified by:
MODEL1610240000.
To cite BioModels Database, please use:
BioModels Database:
An enhanced, curated and annotated resource for published
quantitative kinetic models.
To the extent possible under law, all copyright and related or
neighbouring rights to this encoded model have been dedicated to
the public domain worldwide. Please refer to
CC0
Public Domain Dedication for more information.
2017-06-08 | MODEL1610240000 | BioModels
Project description:<p>We are studying the natural history, pathogenesis and treatment of patients with WHIM syndrome, an immunodeficiency disorder characterized by warts, hypogammaglobulinemia, recurrent infections and neutropenia usually due to autosomal dominant gain-of-function mutations in chemokine receptor <i>CXCR4</i>. We have identified a patient born with WHIM syndrome and the WHIM mutation <i>CXCR4<sup>R334X</sup></i> who has been disease-free for 20 years and who lacks <i>CXCR4<sup>R334X</sup></i> in myeloid cells, the cells that drive disease manifestations. She is a genetic and hematopoietic mosaic, since she still has the mutation in lymphoid cells and non-hematopoietic cells. Cytogenetics and microarray analysis revealed that the mechanism of loss of the mutation was deletion of the mutant allele from one copy of chromosome 2. Whole genome sequencing of patient neutrophil and skin fibroblast genomic DNA revealed that the mechanism of deletion was chromothripsis, a process of chromosome shattering resulting in deletions and rearrangements of the non-deleted chromosomal segments. In the patient, this process evidently occurred in a single hematopoietic stem cell (HSC), resulting in deletion of the disease allele <i>CXCR4<sup>R334X</sup></i> and one copy of 163 other genes on chromosome 2. This HSC evidently acquired a growth advantage and repopulated the HSC population and the myeloid lineage. Consistent with this, studies using gene targeted mice in competitive bone marrow transplantation experiments revealed that selective <i>Cxcr4</i> haploinsufficiency (inactivation of one copy of <i>Cxcr4</i> and not of any other genes) was sufficient to confer a strong engraftment advantage over bone marrow cells from wild type mice as well as bone marrow cells from a mouse model of WHIM syndrome. These results suggest that <i>CXCR4</i> knockdown may be a useful strategy to enhance bone marrow engraftment in the absence of toxic bone marrow conditioning regimens.</p>
| phs000856 | dbGaP
Project description:Hematopoietic stem and progenitor cells (HSPCs), including the multipotent progenitors (MPPs), are responsible for replenishing immune cells. They reside in bone marrow (BM) endosteal and (peri)-vascular niches, which provide all cellular and molecular components required for their lifelong maintenance and fate. Among them, the CXCL12 chemokine and one of its receptor, CXCR4, exert a dominant role in promoting HSPC retention and quiescence. These processes are deregulated in the WHIM Syndrome (WS), a rare immunodeficiency caused by inherited heterozygous autosomal gain-of-function CXCR4 mutations that affect homologous desensitization of the receptor. Clinically, WS is notably characterized by severe, chronic circulating lymphopenia whose mechanisms remain to be elucidated. Using a mouse model carrying a naturally occurring WS-linked Cxcr4 mutation, we explored the possibility that the lymphopenia in WS originates from defects at the MPP level in BM. The global strategy consists in performing high-throughput RNA-seq analyses of the different MPP subsets bearing or not the WS-linked Cxcr4 mutation to investigate the impact of the gain-of-Cxcr4-function on the molecular identity of MPP subsets.
2021-09-02 | GSE182992 | GEO
Project description:Lymphoid primed multipotent progenitors are a subset of MPPs that are undergoing specification to the lymphoid and myeloid cell fates. The transcription factors Lyl1 and E2A are both essential for the development LMPPs and can form a heterodimeric complex. We examined the consequences of E2A- or Lyl1-deficiency on development of LMPPs and on their gene expression program in comparison with wild-type LMPPs
2019-02-12 | GSE126402 | GEO
Project description:The ubiquitin ligase Huwe1 regulates stem cell quiescence, maintenance and lymphoid specification by controlling the expression of N-Myc.
2016-08-18 | GSE85488 | GEO
Project description:A dual biomarker signature extracted a stage-specific cytotype according to cell surface expression of CXCR4/FLK-1 after 5 days of spontaneous differentiation from pluripotent stem cells. Genome-wide microarray analysis revealed a high degree of similarity between CXCR4+/FLK-1+ and CXCR4-/FLK-1- subpopulations at day 5, yet the divergent gene expression profile represents more than 700 unique transcripts. Functional analysis of the 294 up-regulated and 440 down-regulated transcripts that distinguished CXCR4+/Flk-1+ from CXCR4-/Flk-1- subpopulations identified an overt ontologic prioritization of “Cardiovascular Development”-IPA 7.0, 2009.Thus, a biomarker-selected subpopulation from spontaneously differentiated pluripotent stem cells identifies a pool of genes that non-stochastically integrate into a blueprint providing instructions for cardiac lineage-specification. Keywords: Comparison of day 5 embryonic stem cell progenity: CXCR4/FLK-1 biomarker positive versus biomarker negative cells Differentiating embryonic stem cells were FACS sorted at day 5 based on a dual CXCR4/FLK-1 biomarker signature and double positive and double negative progeny were thus collected. Day 5 sorted progeny were independently collected to provide raw material for three biological replicates for each experimental condition. In this manner, three CXCR4/FLK-1 double positive biological samples, and three CXCR4/FLK-1 double negative biological samples were obtained. Total RNA was extracted from each of the samples and RNA pools were profiled on Affymetrix Mouse 430 2.0 Arrays to identify global gene expression changes between double positive and double negative progeny at day 5 of differentiation.
2011-03-11 | E-GEOD-20841 | biostudies-arrayexpress
Project description:Lymphoid primed multipotent progenitors are a subset of MPPs that are undergoing specification to the lymphoid and myeloid cell fates. The transcription factors Lyl1 and E2A are both essential for the development LMPPs and can form a heterodimeric complex. We examined the consequences of E2A- or Lyl1-deficiency on development of LMPPs and on their gene expression program in comparison with wild-type LMPPs We used microarray data to examine the differences in gene expression between control, E2A-/- and Lyl1-/- CD138+ LSK cells.
2019-02-07 | GSE126148 | GEO