The docking protein FRS2␣ is a major mediator of fibroblast growth factor (FGF) signaling. However, the physiological role of FRS2␣ in vivo remains unknown. In this report, we show that Frs2␣-null mouse embryos have a defect in anterior-posterior (A-P) axis formation and are developmentally retarded, resulting in embryonic lethality by embryonic day 8. We demonstrate that FRS2␣ is essential for the maintenance of self-renewing trophoblast stem (TS) cells in response to FGF4 in the extraembryonic ectoderm (ExE) that gives rise to tissues of the placenta. By analyzing chimeric embryos, we found that FRS2␣ also plays a role in cell movement through the primitive streak during gastrulation. In addition, experiments are presented demonstrating that Bmp4 expression in TS cells is controlled by mitogen-activated protein kinase-dependent FGF4 stimulation. Moreover, both the expression of Bmp4 in ExE and activation of Smad1/5 in epiblasts are reduced in Frs2␣-null embryos. These experiments underscore the critical role of FRS2␣ in mediating multiple processes during embryonic development and reveal a potential new link between FGF and Bmp4 signaling pathways in early embryogenesis.

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SummaryVisceral adiposity in elderly is associated with alterations in adipose tissue immune cells leading to inflammation and metabolic dysfunction. The Nlrp3 inflammasome is a critical regulator of macrophage activation, inflammation, and immunometabolism in visceral adipose tissue during aging; however, the potential contribution of adipose tissue B cells is unexplored. Here, we show that aging expands adipose-resident B cells and fat-associated lymphoid clusters (FALCs) in visceral white adipose tissue. Adipose tissue B cells exhibit a memory-like B cell profile similar to the phenotype of aged B cells that are increased in spleen of old mice. Mechanistically, the age-induced FALC formation and adipose B cell expansion, but not B cell transcriptional program, is dependent on the Nlrp3 inflammasome. Furthermore, B cell depletion in aged mice restores lipolysis and defense against loss of core body temperature during cold stress. These data reveal that inhibiting Nlrp3-dependent B cell accumulation can be targeted to reverse metabolic impairment in aging adipose tissue.Highlights- Adipose-resident aged B cells are increased in fat-associated lymphoid clusters (FALC)- FALC formation and adipose-resident B cell expansion during aging are regulated by the Nlrp3 inflammasome- Nlrp3 and B cell depletion in aging restores lipolysis and improves cold tolerancea

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Whole biopsy studies with RNA sequencing or gene arrays elucidated the immune pathways characterizing atopic dermatitis/AD, leading to development of targeted therapeutics. However, single-cell gene profiling is key for identifying rare populations and cell-specific AD biomarkers. To classify cell types and assess transcriptomic changes in lesional/LS and nonlesional/NL skin of AD patients (n¼5) versus controls (n¼7), we performed single-cell RNAseq with 10x Genomics. We isolated 23,124, 7,035, and 10,433 cells from healthy, NL, and LS skin, respectively, capturing major cutaneous cell types. Rare cell populations were also observed, including KRT79 + keratinocytes lining upper hair follicles, PROX1 + /LYVE1lymphatic endothelial cells, and a population of CCL1 + cells unique to AD lesions, co-expressing immune, keratinocyte, and endothelial markers. LS keratinocytes had higher frequency KRT1/ 10 + cells and genomic dysregulation of hyper-proliferative keratins (KRT6A/16) and products of Th2 (CCL2/CCL27), Th17/Th22 (S100A7/8/9), and interferon (IFITM1/3). Generally, immune cells (T-cells including tissue resident memory T-cells/Trm, NK T-cells, Langerhans cells, dendritic cells/DCs, inflammatory epidermal DCs/IDECs), but not macrophages, were expanded in LS AD. LS AD T-cells had increases in Th2 (IL-13), Th22 (IL-22), and a proliferating T-cell population (MKI67). LS skin showed increases in Th2 chemokines (CCL13/ CCL17/CCL18/CCL22), mainly produced by DCs and macrophages, and in SELE, a cell adhesion gene, in vascular endothelium. A unique population of COL6A5/6 + fibroblasts, producing chemokines CCL2/CCL19, was exclusive to LS AD. Overall, scRNA-seq provides insight into AD-related cell composition and suggests that novel CCL19-producing fibroblasts might orchestrate lymphoid organization and inflammation in AD.