A unique function for cyclin D3 in early B cell development.

During hematopoiesis, stem cell proliferation is dependent on expression of the D-type cyclins. However, little is known about how each cyclin D contributes to the development of specific hematopoietic lineages. Here, analysis of Ccnd1(-/-), Ccnd2(-/-), Ccnd3(-/-) and Ccnd2(-/-)Ccnd3(-/-) mice showed that cyclin D3 was uniquely required for the development of pre-B cells. Transcription of Ccnd3 was dependent on expression of the common gamma-chain. In contrast, expression of the pre-B cell receptor and activation of 'downstream' signaling pathways prevented proteasome-mediated degradation of cyclin D3. Cyclin D3 has a key function in B cell development by integrating cytokine and pre-B cell receptor-dependent signals to expand the pool of pre-B cells that have successfully rearranged immunoglobulin heavy chain.

Selection of B lymphocytes in the periphery is determined by the functional capacity of the B cell antigen receptor.

Within the B cell antigen receptor (BCR), the cytoplasmic tails of both Igalpha and Igbeta are required for normal B cell development and maturation. To dissect the mechanisms by which each tail contributes to development in vivo, Igbeta(-/-) mice were reconstituted with retroviruses encoding either wild-type Igbeta, an Igbeta molecule lacking a cytoplasmic tail (Igbeta(deltaC)) or one in which the cytoplasmic tail was derived from Igalpha (Igbeta(Calpha)). All constructs rescued B cell development and generated immature B cell populations in the bone marrow with similar expression levels of both Igbeta and membrane-bound IgM. In the periphery, receptor-surface density was inversely proportional to the number of Igalpha tails in the BCR. Although peripheral-surface-receptor levels differed, splenic B cells expressing either Igbeta or Igbeta(Calpha) responded similarly to stimulation through the BCR. Analysis of membrane-bound IgM and Igbeta expression revealed that peripheral-receptor expression was primarily determined by positive selection between the bone marrow and peripheral immature B cell populations. These data indicate that B cells are selected into the periphery on the basis of a common level of antigen responsiveness.