Neurodevelopmental origins of structural and psychomotor defects in CXCR4-linked primary immunodeficiency
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1108246 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR28910548_1.fastq.gz | Fastqsanger.gz | |||
| SRR28910548_2.fastq.gz | Fastqsanger.gz | |||
| SRR28910549_1.fastq.gz | Fastqsanger.gz | |||
| SRR28910549_2.fastq.gz | Fastqsanger.gz |
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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.
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Project description:The pregnant decidua is infiltrated by many immune cells which are thought to originate in the bone marrow (BM) promoting pregnancy. CXCR4 is a key regulator of the development of NK cells and dendritic cells, both of which play an important role in early placental development and immune tolerance at the maternal-fetal interface. However, the role of CXCR4 in pregnancy is not well understood. To generate tamoxifen-inducible CXCR4 knockout mice, we used the Cre/LoxP tamoxifen-inducible system. For animal experiments, Cre+/CXCR4fl/fl mice and their Cre-/CXCR4fl/fl littermates were used. After tamoxifen treatment, we refer to Cre-/CXCR4fl/wt mice as WT (wild type), and Cre+/CXCR4fl/null mice as CXCR4 KO (knockout). For adoptive bone marrow transplant (BMT) experiments, BMT was performed from either WT GFP transgenic male donor mice into WT or CXCR4 KO females, or from CXCR4 KO male donors into CXCR4 KO females as negative control. Collectively, our study found an important role for maternal CXCR4 expression in immune cell function, placental development and pregnancy maintenance.
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