The Cyclin D1 is a master regulator of lymphoid lineage division and differentiation

DIEGO LADERACH, FLORENCE VASSEUR, MIGUEL FERREIRA, BENEDITA ROCHA

MADRID, SPAIN

Congreso; I Workshop DIFHEMAT-CM From lymphoid differentiation to Cancer; 2009

Centro Nacional de Investigaciones Cardiovasculares (CNIC)

The Cyclin D1 is a master regulator of lymphoid lineage division and differentiation Processes of expansion and differentiation are finely regulated in immune organs to assure the production of competent lymphocytes. Regulation of cell cycle properties is one of the control points of such events. It is therefore important to understand the regulation of the cell cycle machinery in lymphocytes. D-type cyclins are early molecular regulators of such machinery. They control the ability of cyclin dependent kinases (CDKs) to phosphorylate the retinoblastome protein, thus activate of E2F transcription factors and induce the transcriptional activation of genes associated with proliferation. By using quantitative RT-PCR we confirmed that cyclin D2 and cyclin D3 are the most abundant cyclins in thymocyte subpopulations. Their roles in T cell development have been partially studied by gain and loss of function experiments. Under normal situations, cyclin D1 is expressed at low levels in lymphocytes with higher levels in immature/progenitor cells. Analysis of cyclin D1 deficient mice demonstrated a reduction in thymus size and cell numbers in 20-30% of mice. This reduction in absolute numbers is associated with phenotype alterations, a relative accumulation at the level of triple negative TN1 (lin-CD44+CD25-) subpopulation. Accumulation of early B cell progenitors in the bone marrow was observed in the same mice. In lymph nodes and spleens, an important reduction of T and B lymphocytes was also evident. Different mechanistic abnormalities were observed in lymphoid cells. First, reduced cell death associated with increased Bcl-2 levels were detected. Second, reduction in the proliferation capacity may be responsible for such quantitative reductions and precursor accumulation. Finaly, different phenotype alterations were observed that precludes to an abnormal activation. However, 50-80% of mice (depending of the age at which analysis is performed) develop a normal immune system, implying some complex compensatory mechanisms in such mice.  Our results that include confirmation of such effects using in vitro and in vivo RNA interference systems straigh an important role of cyclin D1 for normal T and B cell development, while dispensable for differentiation of non-lymphoid lineages.