Compensation by tumor suppressor genes during retinal development in mice and humans

• Main Authors: Johnson Dianna, Martins Rodrigo, Schweers Brett, Donovan Stacy L, Dyer Michael A
• Format: Article
• Language: English
• Published: BMC 2006-05-01
• Series: BMC Biology
• Online Access: http://www.biomedcentral.com/1741-7007/4/14

<p>Abstract</p> <p>Background</p> <p>The <it>RB1 </it>gene was the first tumor suppressor gene cloned from humans by studying genetic lesions in families with retinoblastoma. Children who inherit one defective copy of the <it>RB1 </it>gene have an increased susceptibility to retinoblastoma. Several years after the identification of the human <it>RB1 </it>gene, a targeted deletion of <it>Rb </it>was generated in mice. Mice with one defective copy of the <it>Rb </it>gene do not develop retinoblastoma. In this manuscript, we explore the different roles of the Rb family in human and mouse retinal development in order to better understand the species-specific difference in retinoblastoma susceptibility.</p> <p>Results</p> <p>We found that the Rb family of proteins (Rb, p107 and p130) are expressed in a dynamic manner during mouse retinal development. The primary Rb family member expressed in proliferating embryonic retinal progenitor cells in mice is p107, which is required for appropriate cell cycle exit during retinogenesis. The primary Rb family member expressed in proliferating postnatal retinal progenitor cells is Rb. p130 protein is expressed redundantly with Rb in postmitotic cells of the inner nuclear layer and the ganglion cell layer of the mouse retina. When Rb is inactivated in an acute or chronic manner during mouse retinal development, p107 is upregulated in a compensatory manner. Similarly, when p107 is inactivated in the mouse retina, Rb is upregulated. No changes in p130 expression were seen when p107, Rb or both were inactivated in the developing mouse retina. In the human retina, RB1 was the primary family member expressed throughout development. There was very little if any p107 expressed in the developing human retina. In contrast to the developing mouse retina, when <it>RB1 </it>was acutely inactivated in the developing human fetal retina, p107 was not upregulated in a compensatory manner.</p> <p>Conclusion</p> <p>We propose that intrinsic genetic compensation between Rb and p107 prevents retinoblastoma in Rb- or p107-deficient mice, but this compensation does not occur in humans. Together, these data suggest a model that explains why humans are susceptible to retinoblastoma following <it>RB1 </it>loss, but mice require both <it>Rb </it>and <it>p107 </it>gene inactivation.</p>