Tyro-3 family receptors are essential regulators of mammalian spermatogenesis.
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.
Lu
Q
Q
Molecular Neurobiology Laboratory, Salk Institute for Biological Studies, La Jolla, California 92037, USA.
Gore
M
M
Zhang
Q
Q
Camenisch
T
T
Boast
S
S
Casagranda
F
F
Lai
C
C
Skinner
M K
MK
Klein
R
R
Matsushima
G K
GK
Earp
H S
HS
Goff
S P
SP
Lemke
G
G
D000818:Animals; D015870:Gene Expression; D036341:Intercellular Signaling Peptides and Proteins; D007985:Leydig Cells / Q000502:physiology; D008024:Ligands; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D019006:Neural Cell Adhesion Molecules / Q000235:genetics; D015513:Oncogene Proteins / Q000235:genetics; D010641:Phenotype; D017293:Protein S; D011506:Proteins; D011518:Proto-Oncogene Proteins; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000502:physiology*; D012708:Sertoli Cells / Q000502:physiology*; D013091:Spermatogenesis / Q000235:genetics / Q000502:physiology*; D000076202:c-Mer Tyrosine Kinase; D000094963:Axl Receptor Tyrosine Kinase; D000099255:Growth Arrest-Specific Protein 6
D036341:Intercellular Signaling Peptides and Proteins; D008024:Ligands; D019006:Neural Cell Adhesion Molecules; D015513:Oncogene Proteins; D017293:Protein S; D011506:Proteins; D011518:Proto-Oncogene Proteins; D020794:Receptor Protein-Tyrosine Kinases; D000076202:c-Mer Tyrosine Kinase; D000094963:Axl Receptor Tyrosine Kinase; D000099255:Growth Arrest-Specific Protein 6; C490767:Mertk protein, mouse; C084944:TYRO3 protein, human; C000722290:AXL receptor tyrosine kinase, mouse