Abnormal spermatogenesis in RXR beta mutant mice.

Abstract

We have generated mouse lines in which the RXRI3 gene was disrupted by homologous recombination. Approximately 50% of the RXR~ homozygous mutants died before or at birth, but those that survived appeared normal except that the males were sterile, owing to oligo-astheno-teratozoospermia. Failure of spermatid release occurred within the germinal epithelium, and the epididymis contained very few spermatozoa that, in addition, exhibited abnormal acrosomes and tails. There was a progressive accumulation of lipids within the mutant Sertoli cells, which were histochemically characterized as unsaturated triglycerides. In old mutant males, progressive degeneration of the germinal epithelium occurred, ending with the formation of acellular lipid-filled tubules. The selective expression of RXR[~ in Sertoli cells, together with the timing of appearence of the histological abnormalities, suggests that the primary defect resulting from the mutation resides in these cells.

Retinoids and spermatogenesis: Lessons from mutant mice lacking the plasma retinol binding protein

“…During the progression of VAD, this defect precedes the onset of testis degeneration. Of interest, a similar spermiation failure has been observed in rats under VAD conditions (Huang and Marshall, 1983;Huang et al, 1988), as well as in Rara-or Rxrb-null mutant mice (Lufkin et al, 1993;Kastner et al, 1996;Mascrez et al, 2004;Chung et al, 2005). Altogether, these data suggest that spermiation requires RA-liganded RAR␣/RXR␤ heterodimers in the seminiferous epithelium.…”

“…Second, the outcome of VAD in the seminiferous epithelium differs between these species: in VAD rats, spermatogenesis is arrested at the preleptotene spermatocyte stage (Huang and Humbree, 1979;Huang et al, 1990;Ismail et al, 1990), whereas in VAD mice, it is arrested at the spermatogonia stage (Huang and Hembree, 1979;Gaemers et al, 1997). Third, the functions of retinoid receptors in vivo are documented from the analysis of genetically altered mouse models (Lufkin et al, 1993;Kastner et al, 1996;Mascrez et al, 2004;Chung et al, 2005;Liu and Gudas, 2005) but not from rat models.…”

“…Altogether, these data suggest that spermiation requires RA-liganded RAR␣/RXR␤ heterodimers in the seminiferous epithelium. This process is unlikely to require a cell-autonomous action of RA in spermatids, as neither RAR␣ nor RXR␤ are detected in these cells (Kastner et al, 1996;Vernet et al, 2006). A slow, chronic, desquamation of immature germ represents another early feature of VAD in the Rbp4-null mutant mice.…”

Functional specificity of the two retinoic acid receptor RAR and RXR families in myogenesis

“…Indeed, the recent phenotypic characterization of all combinations of RXR (either a, b or g)/RAR (either a, b or g) compound mutants has provided genetic evidence supporting the proposal that RXR-RAR heterodimers act as functional units transducing the retinoid signal in vivo and furthermore has indicated that RXRa is the functionally predominant RXR in vivo (Kastner et al, , 1996a. In addition, it has been shown that RXRa null mutants are resistant to RA-induced limb defects (Sucov et al, 1995).…”

“…This is supported by the presence of retinoids in myogenic precursor cells (Wagner et al, 1990(Wagner et al, , 1992Chen et al, 1992) and RA-receptors in muscle tissue Dolle et al, 1994;GigueÁ re, 1994). However, the knock-outs of RARs and RXRs in the mouse to date did not compromise skeletal muscle development (Kastner et al, , 1996bSucov et al, 1994;Lohnes et al, 1995;Krezel et al, 1996) probably due to a large degree of functional redundancy among these receptors which prevented a de®nitive assignment of their physiological functions in the animal. To disable completely the retinoid pathway in skeletal muscle, it will be necessary to generate multiple knock-outs of RARs and RXRs.…”