Multi-level regulation of cyclin D3 controls pre-B cell expansion

During hematopoiesis, stem cell proliferation is dependent upon expression of the D-type cyclins. However, little is known about how each cyclin D contributes to the development of specific hematopoietic lineages. Analysis of Ccnd1-/-, Ccnd2-/-, Ccnd3-/- and Ccnd2-/-Ccnd3-/- mice revealed that cyclin D3 is uniquely required for the proliferative expansion of pre-B cells. Transcription of Ccnd3 is activated before the pro-B stage of development in a process dependent on expression of the common gamma chain of cytokine receptors. In contrast, expression of the pre-BCR and the activation of downstream signaling pathways involving Src and PI3K, but not BLNK, prevent proteasome-mediated cyclin D3 degradation. Additionally signaling through the IL-7 receptor regulates cyclin D3 expression via a mechanism independent of protein stability or transcription, possibly through translational regulation. Cyclin D3 plays a key role in B cell development by integrating cytokine and pre-BCR dependent signals at the appropriate developmental stage in order to expand the pool of pre-B cells that have successfully rearranged immunoglobulin heavy chain.