Cell intrinsic Wnt4 influences cDC fate determination to suppress Type 2 immunity
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA544073 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR9102816.fastq.gz | Fastqsanger.gz | |||
| SRR9102817.fastq.gz | Fastqsanger.gz | |||
| SRR9102818.fastq.gz | Fastqsanger.gz | |||
| SRR9102819.fastq.gz | Fastqsanger.gz |
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Project description:We demonstrate that Wnt4, a beta-catenin independent Wnt ligand, is produced by both hematopoietic and non-hematopoietic cells and is both necessary and sufficient for pre-cDC1/cDC1 maintenance. Whereas BM cDC precursors undergo phosphoJNK/c-Jun activation upon Wnt4 treatment, loss of cDC Wnt4 in CD11cCreWnt4flox/flox mice impaired differentiation of CD24+, Clec9A+, CD103+ cDC1 compared to CD11cCre controls. Conversely, sc-RNAseq analysis of BM revealed a 2-fold increase in cDC2 gene signature genes and flow cytometry demonstrated increased numbers of SIRP-α + cDC2 amid lack of Wnt4. Increased cDC2 numbers due to CD11c-restricted Wnt4 deficiency increased interleukin 5 production, group 2 innate lymphoid cell (ILC2) expansion, and host resistance to the hookworm parasite Nippostrongylus brasiliensis. Collectively, these data uncover a novel and unexpected role for Wnt4 in cDC subset differentiation and Type 2 immunity.
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Project description:Whether conventional dendritic cells (cDC) acquire subset identity under direction of Wnt family glycoproteins is unknown. We demonstrate that Wnt4, a ?-catenin-independent Wnt ligand, is produced by both hematopoietic and nonhematopoietic cells and is both necessary and sufficient for preconventional DC1/cDC1 maintenance. Whereas bone marrow cDC precursors undergo phosphoJNK/c-Jun activation upon Wnt4 treatment, loss of cDC Wnt4 in CD11cCreWnt4flox/flox mice impaired differentiation of CD24+, Clec9A+, CD103+ cDC1 compared with CD11cCre controls. Conversely, single-cell RNA sequencing analysis of bone marrow revealed a 2-fold increase in cDC2 gene signature genes, and flow cytometry demonstrated increased numbers of SIRP-?+ cDC2 amid lack of Wnt4. Increased cDC2 numbers due to CD11c-restricted Wnt4 deficiency increased IL-5 production, group 2 innate lymphoid cell expansion, and host resistance to the hookworm parasite Nippostrongylus brasiliensis Collectively, these data uncover a novel and unexpected role for Wnt4 in cDC subset differentiation and type 2 immunity.
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Project description:To find the differences between β cells expressing Wnt4 and those that do not express it (or express it at low levels) at neonatal stage, murine islets at postnatal day 1 (P1) were collected. Based on a reporter expressing Cre recombinase from the Wnt4 locus, we observed that Wnt4 expression starts in a small subset of β cells at embryonic day (E) 18.5. At neonatal stages, around 50% of β cells express Wnt4 at P0 and most of cells express it by P5. We collected Wnt4 high and Wnt4 low islet cells by FACS and compared their gene expression profile. Wnt4 high islet cell population showed a significant increase of β-cell maturation and function related genes, including transcription factors such as Pdx1 and Nkx6.1, insulin 2, glucokinase (Gck), and the glucose transporter Slc2a2. On the contrary, Wnt4 low islet cell population showed significant increasing of proliferation markers such as Pcna, Mki67 and the positive cell cycle regulators Ccnd1, Ccnd3, Ccna2, Cdk1, Cdk2 and Cdk6. Taken together, these results show that Wnt4 expression is higher in more mature but less proliferative β cells.
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Project description:To study the physiological role of WNT4 in the postnatal ovary, a mouse strain bearing a floxed Wnt4 allele was created and mated to the Amhr2tm3(cre)Bhr strain to target deletion of Wnt4 to granulosa cells. Wnt4flox/-;Amhr2tm3(cre)Bhr/+ mice had significantly reduced ovary weights and produced smaller litters (P<0.05). Serial follicle counting demonstrated that, while Wnt4flox/-;Amhr2tm3(cre)Bhr/+ mice were born with a normal ovarian reserve and maintained normal numbers of small follicles until puberty, they had only 25.2% of the normal number of healthy antral follicles. Some Wnt4flox/-;Amhr2tm3(cre)Bhr/+ mice had no antral follicles or corpora lutea and underwent premature follicle depletion. RTPCR analyses of Wnt4flox/-;Amhr2tm3(cre)Bhr/+ granulosa cells and cultured granulosa cells that overexpress WNT4 demonstrated that WNT4 regulates the expression of Star, Cyp11a1 and Cyp19, steroidogenic genes previously identified as downstream targets of the WNT signaling effector CTNNB1. WNT4- and CTNNB1-overexpressing cultured granulosa cells were analyzed by microarray for alterations in gene expression, which showed that WNT4 also regulates a series of genes involved in late follicle development and the cellular stress response via the WNT/CTNNB1 signaling pathway. Together, these data indicate that WNT4 is required for normal antral follicle development, and may act by regulating granulosa cell functions including steroidogenesis.
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