Single-cell analysis of the common lymphoid progenitor compartment reveals functional and molecular heterogeneity

Positive intergenic feedback circuitry, involving EBF1 and FOXO1, orchestrates B-cell fate

“…The CLP compartment is heterogeneous, consisting of cells with different defined lineage potentials, as well as cells already committed to the B-cell fate. The CLP compartment can be segregated into two distinct populations based on the expression of the cell surface marker LY6D (4,5). During the last two decades, a subset of transcriptional regulators have been identified that specify and promote B-cell fate.…”

“…In the CLP compartment, the E2A proteins act in concert with HEB to induce the expression of forkhead box O1 (Foxo1) (8). Although it is well established that Foxo1 is critical for normal B-cell development, the dynamic regulation of Foxo1 expression in the CLP compartment suggested roles for Foxo1 at the earliest progenitor cell stage (5,(9)(10)(11)(12).…”

Early B-cell Factor 1 Regulates the Expansion of B-cell Progenitors in a Dose-dependent Manner

“…3, A and B), suggesting that E2a dose is not critical for lympho/myeloid lineage restriction. The expression of Ly6D is normally associated with a reduction in the ability of lymphoid progenitors to develop into cells of NK-and DClineage (8,37 IgM Ϫ ), the loss of one allele of either Ebf1 or E2a resulted in a 2-3-fold reduction of cell numbers as compared with Wt mice (Fig. 4A).…”

“…1B). In order to investigate the composition of the early lymphoid restricted compartments further, we investigated the expression of Ly6D within the CLP population (8,37). Ly6D is expressed on a subpopulation of the classical CLP that retain B-lineage potential but display reduced NK-and dendritic cell (DC)-lineage potential in vivo and in vitro as well as a reduced T-cell potential in vivo (8,16).…”

“…The reduction of pro-B-cell numbers in the E2a ϩ/Ϫ mice suggested that reduced E2a dose results in a developmental disruption at an early progenitor stage, before the expression of CD19 on the cell surface. Within the Ly6D ϩ compartment, it is possible to detect cells with an activated B-lineage transcriptional program reflected in the expression of the surrogate light chain gene Lambda5 (5, Igll1) (27,37), and in order to investigate B-lineage specification in progenitors from the mutant mice, we crossed E2a-and Ebf1-deficient mice to a reporter mouse carrying a hCD25 reporter gene under the regulatory elements of the 5 promoter (25). Loss of one allele of E2a resulted in a 5-fold reduction of reporter-expressing CD19 Ϫ progenitor cells, whereas the combined monoallelic loss of Ebf1 and E2a did not enhance the phenotype as compared with E2a ϩ/Ϫ mice (Fig.…”