Cell differentiation

All somatic cells of a person carry essentially the same DNA (exceptions: rearranged antigen-receptor genes of lymphocytes and loss of the nucleus in erythrocytes); they differ because they express different genes. During development, cells become progressively committed — first specified (reversible), then determined (irreversible) — and finally differentiated, with characteristic structure and function (e.g. haemoglobin in erythroblasts, myosin in muscle, keratin in keratinocytes). Potency narrows from totipotent to pluripotent, multipotent and unipotent.

Differentiation is driven by extracellular signals — morphogen gradients (Sonic hedgehog, Wnt, BMP/TGF-β, FGF, retinoic acid), contact-dependent Notch signalling and the extracellular matrix — which activate master transcription factors (e.g. MyoD and myogenin in muscle, PU.1 and GATA-1 in blood, SOX9 in cartilage, RUNX2 in bone, PPARγ in fat). Their effects are locked in by epigenetic marks (DNA methylation, histone modifications), so differentiated states are stable and heritable through cell division. Terminally differentiated cells often leave the cell cycle permanently.

Differentiation can be reversed experimentally: John Gurdon's nuclear transfer (1962) showed that a differentiated nucleus can still direct development, and Shinya Yamanaka (2006) reprogrammed adult cells into induced pluripotent stem (iPS) cells with four transcription factors — Oct4, Sox2, Klf4 and c-Myc (Nobel Prize 2012).