Functions of platelet-derived growth factor-A during organogenesis

Abstract

The formation of organs during embryonic development is calledorganogenesis. This process is regulated by the genes residing in the genome.Thousands of genes are likely to be involved, but there are increasing evidence thatmost organs develop through similar processes performed by conserved networks ofgene products from the same multi-gene families.Platelet-derived growth factor-A (PDGF-A) is a classical growth factor thatexerts its function via a receptor tyrosine kinase, PDGF receptor-á (PDGFR-á). Micedeficient for PDGF-A and PDGFR-á have been analysed in order to elucidate thefunction of PDGF-A in vivo. Deletion of either gene leads to perturbed developmentof several organ systems.In the central nervous system, PDGF-A is critical for the proliferation andspreading of oligodendrocyte progenitors. Loss of PDGF-A leads to defectiveoligodendrogenesis and hypomyelination.In the lung, PDGF-A is critical for multiplication and spreading ofmesenchymal alveolar smooth muscle cell progenitors along the branching bronchialtree. Loss of PDGF-A leads to loss of alveolar smooth muscle cells resulting in a lungdefect reminiscent of lung emphysema.In the skin, PDGF-A is proposed to promote proliferation of a subset ofPDGFR-á positive mesenchymal cells. These cells are subsequently recruited tobecome dermal fibroblasts and the mesenchymal components of the hair follicle: thedermal papilla and the dermal sheath. Lack of PDGF-A leads to fewer cells at theselocations, causing malformed hair follicles, thinner hair and failure to enter the secondhair cycle.A similar role is suggested for PDGF-A in the intestine. PDGF-A promotesproliferation of a subset of PDGFR-á positive mesenchymal progenitor cells that areinvolved in villus formation. At the onset of villus formation, these cells form clusters(called villus clusters) that remain localised at the tip of the growing villus. Our dataimplicate that the villus cluster is instrumental in villus morphogenesis. In the absenceof either PDGF-A or PDGFR-á , fewer villi are formed and those generated areabnormal in size and shape.In summary, we suggest that PDGF-A is a component in one of the conservedgene product networks, where the general principle for PDGF-A is to promoteproliferation (and possibly spreading at some locations) of progenitor cells thatsubsequently differentiate into cell types with important functions in organogenesis.In the lung, skin and hair follicles, and the gastrointestinal villus, the PDGF-A dependent cells are important in epithelial folding.