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B Cell Development Arrest Upon Insertion of a neo Gene Between J_H and Eµ: Promoter Competition Results in Transcriptional Silencing of Germline J_H and Complete V(D)J Rearrangements¹

Laurent Delpy^*, Catherine Decourt^*, Marc Le Bert and Michel Cogné^2,*

^* Laboratoire d’Immunologie, Centre National de la Recherche Scientifique, Faculté de Médecine, Limoges, France; and Centre de Développement des Techniques Avancées pour l’Expérimentation Animale, Centre National de la Recherche Scientifique, Orleans, France

Previous targeting experiments within the IgH locus have shown that V(D)J recombination was affected by an insertion of a neo gene within Eµ upstream of the core enhancer, but not by insertions downstream of the enhancer. Similarly, class switch recombination to a given (C) gene was affected only by interposition of neo in between that gene and the 3' IgH enhancers. Here we show that insertion of neo upstream Eµ only marginally impairs V(D)J recombination, but results in an altered D and J_H gene usage and completely blocks transcription of the germline J_H region and the rearranged VDJ segments. Although transcriptional silencing of J_H occurs upstream of the insertion and results in the lack of mature B cells in homozygous mutant animals, IgH transcription is maintained downstream of the insertion together with neo transcription and can be up-regulated by LPS stimulation or upon fusion with plasmacytoma cells. Altogether these data argue for a polarized "neo effect" involving promoter competition and further show that V(D)J rearrangement can be uncoupled from transcription.

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