Cell Lineage Selection Research Articles

ICSBP Directs Bipotential Myeloid Progenitor Cells to Differentiate into Mature Macrophages

During hematopoiesis, myeloid progenitor cells give rise to granulocytes and macrophages. To study the role for ICSBP, a hematopoietic cell-specific transcription factor in myeloid cell development, the gene was introduced into myeloid progenitor cells established from ICSBP −/− mice. ICSBP retrovirus-transduced cells differentiated into mature macrophages with phagocytic activity, which coincided with the induction of specific target DNA binding activity. Similar to macrophages in vivo, ICSBP-transduced cells were growth arrested, expressed many macrophage-specific genes, and responded to macrophage activation signals. Contrary to this, ICSBP transducion led to repression of granulocyte-specific genes and inhibited G-CSF-mediated granulocytic differentiation in these and other myeloid progenitor cells. Together, ICSBP has a key role in the myeloid cell lineage selection and macrophage maturation.

Mutation and selection within the individual.

Selection within the individual may have played a critical and creative role in evolution, boosting the survival chances of mutations beneficial to the cell and the individual, hindering the spread of deleterious mutations, and reducing the genetic load imposed on the population. We review the literature and present new results to describe the effects of cell-lineage selection on the rate and fixation probability of new mutations. Cell-lineage selection can alter these quantities by several orders of magnitude. Cell-lineage selection is especially important in the case of rare recessive mutations, which are hidden from selection at the individual level but may be exposed to selection at cellular level. Because selection within the individual acts as a sieve eliminating deleterious mutations and increasing the frequency of beneficial ones, mutations observed among progeny will have been pre-selected and are more likely to increase cell proliferation than would randomly generated mutations. Although many authors have focused on the potential conflict between selection at the cellular and individual levels, it must be much more common that the two levels act concordantly. When selection at the cell and individual levels act in a cooperative manner, increased rather than decreased opportunity for germline selection will be favored by evolution.

Evolutionary consequences of mutation and selection within an individual.

Whether in sexual or asexual organisms, selection among cell lineages during development is an effective way of eliminating deleterious mutations. Using a mathematical analysis, we find that relatively small differences in cell replication rates during development can translate into large differences in the proportion of mutant cells within the adult, especially when development involves a large number of cell divisions. Consequently, intraorganismal selection can substantially reduce the deleterious mutation rate observed among offspring as well as the mutation load within a population, because cells rather than individuals provide the selective "deaths" necessary to stem the tide of deleterious mutations. The reduction in mutation rate among offspring is more pronounced in organisms with plastic development than in those with structured development. It is also more pronounced in asexual organisms that produce multicellular rather than unicellular offspring. By effecting the mutation rate, intraorganismal selection may have broad evolutionary implications; as an example, we consider its influence on the evolution of ploidy levels, finding that cell-lineage selection is more effective in haploids and tends to favor their evolution.