Receptor Editing and Marginal Zone B Cell Development Are Regulated by the Helix-Loop-Helix Protein, E2A

Abstract

Previous studies have indicated that the E2A gene products are required to initiate B lineage development. Here, we demonstrate that E2A+/− B cells that express an autoreactive B cell receptor fail to mature due in part to an inability to activate secondary immunoglobulin (Ig) light chain gene rearrangement. Both RAG1/2 gene expression and RS deletion are severely defective in E2A+/− mice. Additionally, we demonstrate that E2A+/− mice show an increase in the proportion of marginal zone B cells with a concomitant decrease in the proportion of follicular B cells. In contrast, Id3-deficient splenocytes show a decline in the proportion of marginal zone B cells. Based on these observations, we propose that E-protein activity regulates secondary Ig gene rearrangement at the immature B cell stage and contributes to cell fate determination of marginal zone B cells. Additionally, we propose a model in which E-proteins enforce the developmental checkpoint at the immature B cell stage.

Accelerated Notch-Dependent Degradation of E47 Proteins in Aged B Cell Precursors Is Associated with Increased ERK MAPK Activation

“…However, given the dependency of RAG expression on E2A, it may be that these pro-B cells in aged mice are compromised in their further development. As shown herein and by others (20), modest alterations in E2A-encoded protein expression, as seen in young E2A heterozygous mice, are capable of limiting B lymphopoiesis. Aged mice do express, as shown here, a smaller pool of early B cell precursors capable of high E47 protein levels.…”

“…E2A-encoded protein expression may change during progressive stages of B lymphopoiesis (20,21). Because B cell precursors previously examined (9,12) and above are a mixture of pro-B and early CD43 ϩ pre-B cells, these above results do not distinguish whether reduced E47 protein occurs in both pro-B and early pre-B cell compartments in aged mice.…”

“…We then assessed the expression of the E47 protein in young and aged pro-B/early pre-B cells using cytoplasmic fluorescent staining as described by Quong et al (20). Typically, as shown in Fig.…”

“…Therefore, we tested whether partial loss of E2A-encoded protein expression in young mice was sufficient to affect B cell development at pro-B and pre-B stages as seen in aged mice. Previously, Quong et al (20) showed that E2A heterozygous mice (E2A ϩ/Ϫ ) have ϳ2-fold reductions in late stage pre-B cells. This was confirmed in our analysis of young (2-3 mo.)…”

The dosage of the neuroD2 transcription factor regulates amygdala development and emotional learning

“…copies of the neuroD2 bHLH transcription factor gene are necessary for amygdala development and function. Immune system bHLH proteins have been shown to be haplo-sensitive (32,33). In this study, neuroD2 showed a haploinsufficiency phenotype and regulated amygdala development and function.…”