ErbB4, a receptor tyrosine kinase, coordinates organization of the seminiferous tubules in the developing testis.

Although close to every fifth couple nowadays has difficulty conceiving, the molecular mechanisms behind the decline in human reproduction remain poorly understood. We report here that the receptor tyrosine kinase Erbb4 is a candidate causal gene, because it is expressed in a sexually dimorphic manner and is abundant in the developing and adult testes in the mouse. Sertoli cell-specific Erbb4-knockout mice have a compromised 3-dimensional organization of the testicular seminiferous tubules that affects their fertility. More specifically, adhesion defects are observed in the absence of Erbb4, which are characterized by changes in the expression of laminin-1, N-cadherin, claudin-3, and certain cell-cell junction components between the Sertoli and germ cells. Interestingly, Erbb4 knockout also had an effect on the Leydig cells, which suggests a paracrine influence of Sertoli cells expressing ErbB4. Many of the defects observed in Erbb4-knockout mice are rescued in targeted ERBB4 gain-of-function mice, pointing to a coordination role for ErbB4 in the developing testis. Thus, the ErbB4 receptor tyrosine kinase promotes seminiferous tubule development by controlling Sertoli cell and germ cell adhesion.