Tyro-3 family receptors are essential regulators of mammalian spermatogenesis

We have generated and analysed null mutations in the mouse genes encoding t hree structurally related receptors with tyrosine kinase activity: Tyro 3, Axl, and Mer(1-4). Mice lacking any single receptor, or any combination of two receptors, are viable and fertile, but male animals that lack all three receptors produce no mature sperm, owing to the progressive death of diffe rentiating germ cells. This degenerative phenotype appears to result from a failure of the tropic support that is normally provided by Sertoli cells o f thc seminiferous tubules, whose function depends on testosterone and addi tional factors produced by Leydig cells(5-7). Tyro 3, Axl and Mer are all n ormally expressed by Sertoli cells during postnatal development, whereas th eir ligands, Gas6 and protein S, are produced by Leydig cells before sexual maturity, and by both Leydig and Sertoli cells thereafter. Here we show th at the concerted activation of Tyro 3, Axl and Mer in Sertoli cells is crit ical to the role that these cells play as nurturers of developing germ cell s. Additional observations indicate that these receptors may also be essent ial for the tropic maintenance of diverse cell types in the mature nervous, immune and reproductive systems.