Dataset Information

Retinoblastoma protein plays multiple essential roles in the terminal differentiation of Sertoli cells.

ABSTRACT: Retinoblastoma protein (RB) plays crucial roles in cell cycle control and cellular differentiation. Specifically, RB impairs the G(1) to S phase transition by acting as a repressor of the E2F family of transcriptional activators while also contributing towards terminal differentiation by modulating the activity of tissue-specific transcription factors. To examine the role of RB in Sertoli cells, the androgen-dependent somatic support cell of the testis, we created a Sertoli cell-specific conditional knockout of Rb. Initially, loss of RB has no gross effect on Sertoli cell function because the mice are fertile with normal testis weights at 6 wk of age. However, by 10-14 wk of age, mutant mice demonstrate severe Sertoli cell dysfunction and infertility. We show that mutant mature Sertoli cells continue cycling with defective regulation of multiple E2F1- and androgen-regulated genes and concurrent activation of apoptotic and p53-regulated genes. The most striking defects in mature Sertoli cell function are increased permeability of the blood-testis barrier, impaired tissue remodeling, and defective germ cell-Sertoli cell interactions. Our results demonstrate that RB is essential for proper terminal differentiation of Sertoli cells.

SUBMITTER: Nalam RL

PROVIDER: S-EPMC2775940 | biostudies-literature | 2009 Nov

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Retinoblastoma protein plays multiple essential roles in the terminal differentiation of Sertoli cells.

Nalam Roopa L RL Andreu-Vieyra Claudia C Braun Robert E RE Akiyama Haruhiko H Matzuk Martin M MM

Molecular endocrinology (Baltimore, Md.) 20091009 11

Retinoblastoma protein (RB) plays crucial roles in cell cycle control and cellular differentiation. Specifically, RB impairs the G(1) to S phase transition by acting as a repressor of the E2F family of transcriptional activators while also contributing towards terminal differentiation by modulating the activity of tissue-specific transcription factors. To examine the role of RB in Sertoli cells, the androgen-dependent somatic support cell of the testis, we created a Sertoli cell-specific conditi ...[more]

PMID: 19819985

Similar Datasets

Project description:A broad spectrum of human diseases called ciliopathies is caused by defective primary cilia morphology or signal transduction. The primary cilium is a solitary organelle that responds to mechanical and chemical stimuli from extracellular and intracellular environments. Transmembrane protein 107 (TMEM107) is localized in the primary cilium and is enriched at the transition zone where it acts to regulate protein content of the cilium. Mutations in TMEM107 were previously connected with oral-facial-digital syndrome, Meckel-Gruber syndrome, and Joubert syndrome exhibiting a range of ciliopathic defects. Here, we analyze a role of Tmem107 in craniofacial development with special focus on palate formation, using mouse embryos with a complete knockout of Tmem107. Tmem107-/- mice were affected by a broad spectrum of craniofacial defects, including shorter snout, expansion of the facial midline, cleft lip, extensive exencephaly, and microphthalmia or anophthalmia. External abnormalities were accompanied by defects in skeletal structures, including ossification delay in several membranous bones and enlargement of the nasal septum or defects in vomeronasal cartilage. Alteration in palatal shelves growth resulted in clefting of the secondary palate. Palatal defects were caused by increased mesenchymal proliferation leading to early overgrowth of palatal shelves followed by defects in their horizontalization. Moreover, the expression of epithelial stemness marker SOX2 was altered in the palatal shelves of Tmem107-/- animals, and differences in mesenchymal SOX9 expression demonstrated the enhancement of neural crest migration. Detailed analysis of primary cilia revealed region-specific changes in ciliary morphology accompanied by alteration of acetylated tubulin and IFT88 expression. Moreover, Shh and Gli1 expression was increased in Tmem107-/- animals as shown by in situ hybridization. Thus, TMEM107 is essential for proper head development, and defective TMEM107 function leads to ciliary morphology disruptions in a region-specific manner, which may explain the complex mutant phenotype.

Project description:BackgroundThe non-receptor tyrosine kinase Abelson (Abl) is a key player in oncogenesis, with kinase inhibitors serving as paradigms of targeted therapy. Abl also is a critical regulator of normal development, playing conserved roles in regulating cell behavior, brain development and morphogenesis. Drosophila offers a superb model for studying Abl's normal function, because, unlike mammals, there is only a single fly Abl family member. In exploring the mechanism of action of multi-domain scaffolding proteins like Abl, one route is to define the roles of their individual domains. Research into Abl's diverse roles in embryonic morphogenesis revealed many surprises. For instance, kinase activity, while important, is not crucial for all Abl activities, and the C-terminal F-actin binding domain plays a very modest role. This turned our attention to one of Abl's least understood features-the long intrinsically-disordered region (IDR) linking Abl's kinase and F-actin binding domains. The past decade revealed unexpected, important roles for IDRs in diverse cell functions, as sites of posttranslational modifications, mediating multivalent interactions and enabling assembly of biomolecular condensates via phase separation. Previous work deleting conserved regions in Abl's IDR revealed an important role for a PXXP motif, but did not identify any other essential regions.MethodsHere we extend this analysis by deleting the entire IDR, and asking whether Abl∆IDR rescues the diverse roles of Abl in viability and embryonic morphogenesis in Drosophila.ResultsThis revealed that the IDR is essential for embryonic and adult viability, and for cell shape changes and cytoskeletal regulation during embryonic morphogenesis, and, most surprisingly, revealed a role in modulating protein stability.ConclusionOur data provide new insights into the role of the IDR in an important signaling protein, the non-receptor kinase Abl, suggesting that it is essential for all aspects of protein function during embryogenesis, and revealing a role in protein stability. These data will stimulate new explorations of the mechanisms by which the IDR regulates Abl stability and function, both in Drosophila and also in mammals. They also will stimulate further interest in the broader roles IDRs play in diverse signaling proteins. Video Abstract.

Dataset Information

Retinoblastoma protein plays multiple essential roles in the terminal differentiation of Sertoli cells.

Publications

Retinoblastoma protein plays multiple essential roles in the terminal differentiation of Sertoli cells.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets