High postnatal lethality and testis degeneration in retinoic acid receptor alpha mutant mice.

Lufkin, Thomas; Lohnes, David; Mark, Manuel; Dierich, Andrée; Gorry, Philippe; Gaub, Marie–Pierre; LeMeur, Marianne; Chambon, Pierre

doi:10.1073/pnas.90.15.7225

Cited by 503 publications

(335 citation statements)

References 43 publications

Supporting

Mentioning

315

Contrasting

Unclassified

Order By: Relevance

“…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.…”

Section: Spermiation and Adhesion Of Germ Cells Are Highly Sensitive supporting

confidence: 67%

“…Rara is expressed mainly, if not exclusively, in Sertoli cells (Vernet et al, 2006), and spermatogenesis is dramatically disturbed in Rara-null mutants. Both VAD mice (present report) and Raranull mutants (Lufkin et al, 1993;Chung et al, 2005) display a failure of spermatid release, a degradation of elongated spermatids by Sertoli cells and a chronic desquamation of immature germ cells, thus indicating that the effects of RA on spermiation and on germ cell adhesion to Sertoli cells are mediated by RAR␣. However, Rara-null testes do not show histological features indicative of a delay in spermatogonia differentiation that is most remarkable hallmark of VAD-induced testis degeneration (present report).…”

Section: Rara-null Mutant Mice Display Some But Not All Vad-induced Dmentioning

confidence: 57%

“…Accordingly, the testes of Rbp4-null mice did not display histological abnormalities, at 6 weeks ( Fig. 2E,F) and 1 year of age (not shown), notably defects related to an impaired RA signalling (Lufkin et al, 1993;Ghyselinck et al, 1999). These data indicate that RBP deficiency decreases testis ROL stores.…”

Section: Testicular Vitamin a Stores Are Decreased In Mice Lacking Rbpmentioning

confidence: 66%

“…A slow, chronic, desquamation of immature germ represents another early feature of VAD in the Rbp4-null mutant mice. Loss of germ cell through desquamation has also been described in vitamin A-deficient rats (Unni et al, 1983;Griswold et al, 1989) as well as in mice lacking RAR␣ (Lufkin et al, 1993). These data underline a critical role of RA signalling in maintaining the cohesiveness of the seminiferous epithelium, which may be achieved either by controlling the permeability of Sertoli cell tight junctions (Unni et al, 1983;Huang et al, 1988), or the expression of cell adhesion molecules holding together Sertoli and germ cells (reviewed in Mruk and Cheng, 2004).…”

Section: Spermiation and Adhesion Of Germ Cells Are Highly Sensitive mentioning

confidence: 90%

“…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.…”

Section: Discussionmentioning

confidence: 99%

See 4 more Smart Citations

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

et al. 2006

View full text Add to dashboard Cite

Using Rbp4-null mice as models, we have established for the first time the kinetics of the spermatogenetic alterations during vitamin A deficiency (VAD). Our data demonstrate that the VAD-induced testicular degeneration arises through the normal maturation of germ cells in a context of spermatogonia differentiation arrest. They indicate that retinoic acid (RA) appears dispensable for the transition of premeiotic to meiotic spermatocytes, meiosis, and spermiogenesis. They confirm that RA plays critical roles in controlling spermatogonia differentiation, spermatid adhesion to Sertoli cells, and spermiation, and suggest that the VAD-induced arrest of spermatogonia differentiation results from simultaneous blocks in RA-dependent events mediated by RA receptor ␥ (RAR␥) in spermatogonia and by RAR␣ in Sertoli cells. They also provide evidence that expression of major RA-metabolizing enzymes is increased in mouse Sertoli cells upon VAD and that vitamin A-deficient A spermatogonia differ from their RA-sufficient counterparts by the expression of the Stra8 gene.

show abstract

Section: Spermiation and Adhesion Of Germ Cells Are Highly Sensitive supporting

confidence: 67%

Section: Rara-null Mutant Mice Display Some But Not All Vad-induced Dmentioning

confidence: 57%

Section: Testicular Vitamin a Stores Are Decreased In Mice Lacking Rbpmentioning

confidence: 66%

Section: Spermiation and Adhesion Of Germ Cells Are Highly Sensitive mentioning

confidence: 90%

Section: Discussionmentioning

confidence: 99%

See 3 more Smart Citations

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

et al. 2006

View full text Add to dashboard Cite

show abstract

On the holistic approach in cellular and cancer biology: Nonlinearity, complexity, and quasi-determinism of the dynamic cellular network

Waliszewski

Molski²,

Konarski³

1998

J. Surg. Oncol.

View full text Add to dashboard Cite

A keystone of the molecular reductionist approach to cellular biology is a specific deductive strategy relating genotype to phenotype—two distinct categories. This relationship is based on the assumption that the intermediary cellular network of actively transcribed genes and their regulatory elements is deterministic (i.e., a link between expression of a gene and a phenotypic trait can always be identified, and evolution of the network in time is predetermined). However, experimental data suggest that the relationship between genotype and phenotype is nonbijective (i.e., a gene can contribute to the emergence of more than just one phenotypic trait or a phenotypic trait can be determined by expression of several genes). This implies nonlinearity (i.e., lack of the proportional relationship between input and the outcome), complexity (i.e. emergence of the hierarchical network of multiple cross‐interacting elements that is sensitive to initial conditions, possesses multiple equilibria, organizes spontaneously into different morphological patterns, and is controled in dispersed rather than centralized manner), and quasi‐determinism (i.e., coexistence of deterministic and nondeterministic events) of the network. Nonlinearity within the space of the cellular molecular events underlies the existence of a fractal structure within a number of metabolic processes, and patterns of tissue growth, which is measured experimentally as a fractal dimension. Because of its complexity, the same phenotype can be associated with a number of alternative sequences of cellular events. Moreover, the primary cause initiating phenotypic evolution of cells such as malignant transformation can be favored probabilistically, but not identified unequivocally. Thermodynamic fluctuations of energy rather than gene mutations, the material traits of the fluctuations alter both the molecular and informational structure of the network. Then, the interplay between deterministic chaos, complexity, self‐organization, and natural selection drives formation of malignant phenotype. This concept offers a novel perspective for investigation of tumorigenesis without invalidating current molecular findings. The essay integrates the ideas of the sciences of complexity in a biological context. J. Surg. Oncol. 1998;68:70–78. © 1998 Wiley‐Liss, Inc.

show abstract

Pattern of retinoid-induced teratogenic effects: Possible relationship with relative selectivity for nuclear retinoid receptors RARα, RARβ, and RARγ

et al. 1996

View full text Add to dashboard Cite

Retinoic acid, an oxidative metabolite of vitamin A, is involved in the control of many biological processes including embryonic development. Excess as well as deficiency of retinoids were found to be teratogenic. The effects of retinoids in normal as well as abnormal development may be mediated by two members of retinoid receptors, the RAR's and RXR's, which exhibit a specific temporal and spatial expression during development. The significance of the retinoid receptors was investigated here by studying the teratogenic effects of retinoid ligands with relative selectivity for binding and transactivation of the retinoic acid receptors RARα, RARβ and RARγ. Pregnant NMRI mice were administered 5 or 15 mg/kg of CD 336 (Am 580) (α‐ligand), CD 2019 (β‐ligand), CD 437 (γ‐ligand) or 37.5 mg/kg all‐trans‐retinoic acid in 25% Cremophor EL on day 8.25 or day 11 of gestation by gastric intubation. External, visceral and skeletal malformations were observed on day 18 of gestation. The order of teratogenic potency was: α‐ligand>β‐ligand>γ‐ligand. In addition, these retinoids also produced a different spectrum of defects. The α‐ligand induced the most varied defects including severe ear, mandible, and limb malformations. The β‐ligand induced defects of the urinary system and liver in greater frequency than expected from its relative potency. The γ‐ligand preferentially induced ossification deficiencies and defects of the sternebrae and vertebral body. Our results show that these three retinoids, which were previously demonstrated to exhibit retinoid‐like activities in several systems, exert differing teratogenic activities, in regard to both potency and regioselectivity: we hypothesize that the relative selectivity for binding and transactivation of the three retinoic acid receptors could possibly be related to the differences of teratogenic effects observed in this study. The low potency of the γ‐ligand may lead the way to interesting new retinoids with improved therapeutic ratio. © 1996 Wiley‐Liss, Inc.

show abstract

High postnatal lethality and testis degeneration in retinoic acid receptor alpha mutant mice.

Cited by 503 publications

References 43 publications

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

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

On the holistic approach in cellular and cancer biology: Nonlinearity, complexity, and quasi-determinism of the dynamic cellular network

Pattern of retinoid-induced teratogenic effects: Possible relationship with relative selectivity for nuclear retinoid receptors RARα, RARβ, and RARγ

Contact Info

Product

Resources

About