Only a small number of cells in adult tissues (the stem cells) possess the ability to self-renew at every cell division, while producing differentiating daughter cells to maintain tissue homeostasis for an organism¿s lifetime. A better understanding of stem cells biology will not only reveal the crucial molecular mechanisms that control the formation and maintenance of tissues but will also influence stem cell-based therapies in regenerative medicine and cancer treatments. Much progress has been made in recent years in understanding the molecular mechanisms underlying intrinsic and extrinsic controls of stem cell regulation but the complex network of genetic and epigenetic pathways is only partially understood.
Heterochromatin Protein 1 (HP1) is a dynamic epigenetic determinant mainly involved in heterochromatin formation, epigenetic gene silencing and telomere maintenance. Recently, I found that, in Drosophila melanogaster, HP1 plays a crucial role in the control of GSC homeostasis in female germline. My proposal is focused to understand the molecular mechanism of HP1 function in self-renewal and differentiation of adult neural stem cells and its implication in neurodegenerative diseases.
Stem cells are undifferentiated cells defined by their unique capacity to maintain self-renewing potential at every cell division, while producing differentiating daughter cells to ensure the correct development and to maintain tissues homeostasis. A better understanding of stem cells biology will not only reveal the crucial molecular mechanisms that control the formation and maintenance of tissues, but will also influence stem cell-based therapies in regenerative medicine and cancer treatments. In view of this, deepening the molecular mechanisms that control the fine balance between stem cell self-renewal and differentiation represents one of the fundamental goals of stem cell biology. This balance often depends on the coordinated regulation of complex transcriptional and post-transcriptional hierarchies. A fast growing body of experimental evidence provides strong evidences that epigenetic mechanisms involving chromatin architecture and histone modification are very important for the regulation of stem cells maintenance and differentiation in Drosophila and mammals. However, the epigenetic regulation of adult stem cell function remains poorly defined.
The Drosophila CNS offers a complex but experimentally amenable model for investigating the regulation of stem cell behavior. Drosophila melanogaster is an important model organism used to study the brain development of organisms ranging from insects to mammals; particularly useful for investigating tissue specific gene functions, as there are a wealth of tools, including extensive collections of Gal4 driver stocks.
Finally, Drosophila provides opportunities to test pharmacological treatment of neurological phenotypes.
Despite advancements in the fields of molecular biology, genetics, and pharmaceutical sciences, current biomedical science is a long way from the ultimate goal of appropriate strategies for the effective treatment of these neurodegenerative disorders or for a possible application of stem cells in the treatment of diseases.
I think that the results from my proposed experiments will give an important contribution to understanding the fundamental mechanisms which control the identity and maintenance of somatic stem cells and certainly add a new dimension to our understanding of HP1 targeting and functions in epigenetic regulation of stem cells behavior in Drosophila melanogaster. Furthermore these results highlight provide valuable insights into mammalian stem cell biology as well helping paint a more detailed picture of vertebrate stem cell behavior.
References
Bello B, Reichert H, Hirth F. (2006). Development 133, 2639-2648.
Betschinger J, Mechtler K, Knoblich JA. (2006). Cell 124, 1241-1253.
Brand AH, Livesey FJ. (2011). Neuron 70,719-729.
Breunig JJ, Haydar TF, Rakic P. (2011). Neuron 70, 614-625.
Casale AM, Cappucci U, Fanti L, Piacentini L. (2019). Sci Rep. 9, 4372.
de Carvalho AC. (2014). BMC Proc. 8, O19.
De Lucia F, Ni JQ, Vaillant C, Sun FL. (2005). Nucleic Acids Res 33, 2852-2858.
Dietzl G, Chen D, Schnorrer F, Su KC, Barinova Y, Fellner M, Gasser B, Kinsey K, Oppel S, Scheiblauer S, Couto A, Marra V, Keleman K, Dickson BJ. (2007). Nature 448, 151-156.
Doe CQ. (2008). Development. 135, 1575-1587.
Eissenberg JC, James TC, Foster-Hartnett DM, Hartnett T, Ngan V, Elgin SC. (1990). Proc Natl Acad Sci U S A 87, 9923-9927.
Fanti L, Giovinazzo G, Berloco M, Pimpinelli S. (1998). Mol Cell 2, 527¿538.
Homem CC, Knoblich JA (2012). Development 139, 4297-4310.
James TC, Eissenberg JC, Craig C, Dietrich V, Hobson A, Elgin SC. (1989). Eur J Cell Biol 50, 170-180.
James TC, Elgin SC. (1986). Mol Cell Biol 6, 3862-3872.
Kang KH, Reichert H. (2015). Cell Tissue Res. 359, 33-45.
Kwon SH, Florens L, Swanson SK, Washburn, MP, Abmayr SM, Workman JL. (2010). Genes Dev 24, 2133-2145.
Lee CY, Wilkinson BD, Siegrist SE, Wharton RP, Doe CQ. (2006). Dev Cell 10, 441-449.
Lin CH, Li B, Swanson S, Zhang Y, Florens L, Washburn MP, Abmayr SM, Workman JL. (2008). Mol Cell 32, 696-706.
Lu B, Vogel H. (2009). Annu Rev Pathol. 4, 315-342.
Mahla RS. (2016). Int J Cell Biol 6940283.
Merkle FT, Alvarez-Buylla A. (2006). Curr Opin Cell Biol. 18,704-709.
Neumüller RA, Knoblich JA. (2009). Genes Dev. 23, 2675-2699.
Oh J, Lee YD, Wagers AJ. (2014). Nat Med. 20, 870-880.
Perrini B, Piacentini L, Fanti L, Altieri F, Chichiarelli S, Berloco M, Turano C, Ferraro A, Pimpinelli S. (2004). Mol Cell 15, 467-476.
Piacentini L, Fanti L, Berloco M, Perrini B, Pimpinelli S. (2003). J Cell Biol 161, 707-714.
Piacentini L, Fanti L, Negri R, Del Vescovo V, Fatica A, Altieri F, Pimpinelli S. (2009). PLoS Genet 5, e1000670.
Vakoc CR, Mandat SA, Olenchock BA, Blobel GA. (2005). Mol Cell 19, 381-391.
Yan D, Neumüller RA, Buckner M, Ayers K, Li H, Hu Y, Yang-Zhou D, Pan L, Wang X, Kelley C, Vinayagam A, Binari R, Randklev S, Perkins LA, Xie T, Cooley L, Perrimon N. (2014). Dev Cell. 28, 459-473.
Zhang CL, Huang T, Wu BL, He WX, Liu D. (2017). Oncotarget 8, 75756-75766.