Fate Mapping for Activation-Induced Cytidine Deaminase (AID) Marks Non-Lymphoid Cells During Mouse Development

Philipp C Rommel,Skirmantas Kriaucionis,Gist F Croft,Rafael Casellas,Nathaniel Heintz,Davide F Robbiani,Alexander D Gitlin,David Bosque,Michel C Nussenzweig,Sebastian D Fugmann

doi:10.1371/journal.pone.0069208

Abstract

The Aicda gene encodes Activation-Induced cytidine Deaminase (AID), an enzyme essential for remodeling antibody genes in mature B lymphocytes. AID is also responsible for DNA damage at oncogenes, leading to their mutation and cancer-associated chromosome translocation in lymphoma. We used fate mapping and AIDGFP reporter mice to determine if AID expression in the mouse extends beyond lymphocytes. We discovered that AIDcre tags a small fraction of non-lymphoid cells starting at 10.5 days post conception (dpc), and that AIDGFP+ cells are detectable at dpc 11.5 and 12.5. Embryonic cells are tagged by AIDcre in the submandibular region, where conditional deletion of the tumor suppressor PTEN causes squamous papillomas. AIDcre also tags non-lymphoid cells in the embryonic central nervous system. Finally, in the adult mouse brain, AIDcre marks a small fraction of diverse neurons and distinct neuronal populations, including pyramidal cells in cortical layer IV.

Highlights

Activation-induced cytidine deaminase (AID) is required for somatic hypermutation (SHM) and class switch recombination (CSR), two DNA diversification reactions of mature B lymphocytes
AID is responsible for targeted DNA mutations (SHM) and deletional recombinations (CSR) at the immunoglobulin heavy chain gene of mature B lymphocytes [2,3,4]
Besides being transiently expressed at high levels in B cells during the germinal center reaction, low levels of AID have been reported in developing B cells and in a fraction of T cells [5,6,7,17]

Summary

Introduction

Activation-induced cytidine deaminase (AID) is required for somatic hypermutation (SHM) and class switch recombination (CSR), two DNA diversification reactions of mature B lymphocytes. Upon activation in response to antigen, B cells proliferate, form germinal centers (specialized anatomical structures within lymphoid organs), and express high levels of AID [1]. In addition to its high but transient expression in B cells during the germinal center reaction, low but biologically active amounts of AID have been detected in developing B cells, the significance of this finding is unclear [5,6,7]. Besides physiologically targeting antibody genes, AID is capable of considerable collateral genomic damage. This includes mutations and DNA breaks at cancer genes, which predispose them to participate in lymphomaassociated chromosome translocations [8,9,10,11]. Not surprisingly, many layers regulating AID expression and activity are in place to limit this enzyme’s potential to initiate cancer (reviewed in 11)

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Conclusion