Tyro-3 family receptors are essential regulators of mammalian spermatogenesis

Abstract

We have generated and analysed null mutations in the mouse genes encoding three structurally related receptors with tyrosine kinase activity: Tyro 3, Axl, and Mer. 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 differentiating germ cells. This degenerative phenotype appears to result from a failure of the tropic support that is normally provided by Sertoli cells of the seminiferous tubules, whose function depends on testosterone and additional factors produced by Leydig cells. Tyro 3, Axl and Mer are all normally expressed by Sertoli cells during postnatal development, whereas their ligands, Gas6 and protein S, are produced by Leydig cells before sexual maturity, and by both Leydig and Sertoli cells thereafter. Here we show that the concerted activation of Tyro 3, Axl and Mer in Sertoli cells is critical to the role that these cells play as nurturers of developing germ cells. Additional observations indicate that these receptors may also be essential for the tropic maintenance of diverse cell types in the mature nervous, immune and reproductive systems.

Immunobiology of the TAM receptors

“…Each protein has a ~60 amino-acid Gla domain at its amino terminus, a region rich in glutamic 19 , genuine insights into the biological roles of these receptors were only obtained when mice lacking TYRO3, AXL, MER or GAS6 were generated and analysed [20][21][22][23][24][25] .…”

“…Remarkably, even these triple knockout mice were found to be viable at birth, and to be superficially normal for the first several weeks thereafter. This notwithstanding, mice lacking all three TAM receptors were found to develop a plethora of debilitating phenotypes, all of which appeared to be degenerative in nature 20,21 .…”

“…In contrast to most other receptor PTKs, expression of the TAMs is substantially upregulated postnatally, and is maintained at relatively high levels in adult tissues. Although cDNAs encoding the TAM receptors have been cloned repeatedly from tumour cells, and TAM receptors, particularly AXL, have been implicated in cancer progression 19 , genuine insights into the biological roles of these receptors were only obtained when mice lacking TYRO3, AXL, MER or GAS6 were generated and analysed [20][21][22][23][24][25] .…”

“…Because knockout of each of the TAM genes still produced viable and fertile mice, and because the Tyro3 and Mer genes are linked in the mouse genome, it was possible to generate knockout mice that were deficient for all three TAM receptors 20 . Remarkably, even these triple knockout mice were found to be viable at birth, and to be superficially normal for the first several weeks thereafter.…”

“…Remarkably, even these triple knockout mice were found to be viable at birth, and to be superficially normal for the first several weeks thereafter. This notwithstanding, mice lacking all three TAM receptors were found to develop a plethora of debilitating phenotypes, all of which appeared to be degenerative in nature 20,21 .Beginning at about 3 weeks after birth, for example, germ cells in the testis were observed to die in increasing numbers, such that by three months after birth, the seminiferous tubules in the TAM-deficient mutants were depleted of spermatogonia, spermatocytes, spermatids and mature sperm 20 . Another dramatic phenotype was observed in the retinae of TAM-deficient mice, where, beginning at about the same time, photoreceptors were seen to die by apoptosis.…”