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

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.

Activation-induced cytidine deaminase and active cytidine demethylation

“…This is best illustrated by the conflicting results in iPSCs [33][34][35][36] and heterokaryons [27,29], and by the difficulty in reconciling reports of AID-driven demethylation in the germline [30,31] with the evidence that these cells express little AID [44,63,[65][66][67]. The elucidation of these issues will come from the empirical investigation of the questions listed in Box 1.…”

“…Data from genome-wide demethylation studies [30,34,41,42] duced in mice [63]. Notably, three independently generated Aicda-CrexROSA26-EYFP gene-tracing mouse strains did not find evidence for the transcription of the Aicda locus in the germline and pluripotent tissues ( [65][66][67]; Cortesã o and V.M.B., unpublished), which shows that AID expression, if any, is below the threshold of detection of these tracer lines. Thus, there is currently little evidence that AID is expressed in the germline.…”

Involvement of activation-induced cytidine deaminase in skin cancer development

“…Aicda-Cre and R26R double-Tg mice (Aicda-Cre R26R), in which AID promoterdriven Cre recombinase irreversibly induces lacZ expression, were used to identify cells with a history of AID expression ( Figure 6A and refs. 33,34). Aicda-Cre is a line of bacterial artificial chromosome (BAC) Tg mice that harbor the whole Aicda genomic locus with a targeted insertion of the Cre-coding sequence (35).…”

Deletion of Rb1 induces both hyperproliferation and cell death in murine germinal center B cells

“…These matings did not yield genotypes at expected mendelian frequencies and we were unable to generate AID-Cre- Rb1 F/F -p107 −/− mice. This was likely due to embryonic lethality since AID is expressed in embryonic neuronal cells [22] and Rb1 null mice are embryonic lethal due to neuronal defects [12–14]. …”