RESUMO
In humans, haploinsufficiency of either SOX2 or PAX6 is associated with microphthalmia, anophthalmia or aniridia. In this study, through the genetic spatiotemporal specific ablation of SOX2 on both wild-type and Pax6-haploinsufficent backgrounds in the mouse, we have uncovered a transcriptionally distinct and developmentally transient stage of eye development. We show that genetic ablation of SOX2 in the optic cup results in complete loss of neural competence and eventual cell fate conversion to non-neurogenic ciliary epithelium. This cell fate conversion is associated with a striking increase in PAX6, and genetically ablating SOX2 on a Pax6-haploinsufficient background partially rescues the Sox2-mutant phenotype. Collectively, these results demonstrate that precise regulation of the ratio of SOX2 to PAX6 is necessary to ensure accurate progenitor cell specification, and place SOX2 as a decisive factor of neural competence in the retina.
Assuntos
Corpo Ciliar/citologia , Proteínas do Olho/metabolismo , Proteínas de Homeodomínio/metabolismo , Fatores de Transcrição Box Pareados/metabolismo , Proteínas Repressoras/metabolismo , Fatores de Transcrição SOXB1/metabolismo , Células-Tronco/citologia , Células-Tronco/metabolismo , Animais , Diferenciação Celular/genética , Diferenciação Celular/fisiologia , Proteínas do Olho/genética , Proteínas de Homeodomínio/genética , Imuno-Histoquímica , Hibridização In Situ , Camundongos , Camundongos Mutantes , Neurônios/citologia , Neurônios/metabolismo , Fator de Transcrição PAX6 , Fatores de Transcrição Box Pareados/genética , Proteínas Repressoras/genética , Retina/citologia , Retina/metabolismo , Fatores de Transcrição SOXB1/genéticaRESUMO
Sox2(+) adult mouse pituitary cells can self-renew and terminally differentiate in vitro, but their physiological role in vivo and possible contribution to oncogenesis remain largely unknown. Using genetic lineage tracing, we show here that the Sox2(+) cell compartment of both the embryonic and adult pituitary contains stem/progenitor cells that are able to differentiate into all hormone-producing lineages and contribute to organ homeostasis during postnatal life. In addition, we show that targeted expression of oncogenic ß-catenin in Sox2(+) cells gives rise to pituitary tumors, but, unexpectedly, the tumor mass is not derived from the Sox2(+) mutation-sustaining cells, suggesting a paracrine role of Sox2(+) cells in pituitary oncogenesis. Our data therefore provide in vivo evidence of a role for Sox2(+) stem/progenitor cells in long-term physiological maintenance of the adult pituitary, and highlight an unexpected non-cell-autonomous role for these cells in the induction of pituitary tumors.