Instrinsic an extrinsic influences on the lineage and mode of cell division of progenitors in the developing Zebrafish retina
Final Report Abstract
How the growing animal controls the generation of the correct number and proportion of each type and subtype of nerve cells is under intensive investigation, with relevant implications in stem cell, developmental and evolutionary neuroscience fields. Using the advantage of the zebrafish embryo (they are see-through and develop outside of the mother) and establishing transgenic lines in which fluorescent reporter proteins highlight the expression of specific genes, we revealed how particular subtypes of retinal neurons are sequentially born in vivo, through rounds of cell divisions in their native environment. With an integrated approach of live imaging and functional analysis we demonstrated that cell lineage-dependent intrinsic programs underlie the birth of particular kinds of inhibitory nerve cells. This occurs through coordination of asymmetric cell division and gene expression within excitatory nerve cell progenitors expressing the important excitatory cell fate-specifying gene, ath5. Our study revealed unexpected reproducible sequences of asymmetric cell divisions underlying the generation of such inhibitory and excitatory nerve cells, providing a paradigm for future understandings of cell lineage dependent nerve cell subtype composition of early retinal circuits. Part of this work was carried out in collaboration with Dr. Patricia Jusuf and Dr. Mirana Ramialison (EMBL Australia), leading to three publications, one of which has been selected as a highlight in “This week in the Journal” (by the Journal of Neuroscience) as well as in the Heidelberg University Press Releases (http://www.uniheidelberg.de/presse/news2012/pm20121203_nervenzellen_en.html). A parallel investigative direction aimed to understand cross-regulatory networks of yet unknown nature between the excitatory cell fate-specifying gene ath5 and the asymmetric cell division machinery. This study led to the discovery of a negative feedback loop between Ath5 and the F-actin binding protein Anillin – essential component of the cytokinesis furrow (manuscript currently under revision). Collectively, our results reveal links between Ath5, Anillin and asymmetric inheritance of apically located signalling molecules such as Par3 the Notch regulator Mindbomb (Mib) and F-actin pools. Anillin has been associated to proliferation and metastatic potential of human tumours from many different tissues. Following investigative directions elucidating the role of Anillin as well as its interplay with Ath5 will therefore provide important insights for understanding key mechanisms ensuring adult tissue homeostasis, and how these mechanisms are deregulated in cancer stem cells.
Publications
- (2011). Evolutionary relationships and diversification of barhl genes within retinal cell lineages. Bmc Evolutionary Biology 11
Schuhmacher, L.-N., Albadri, S., Ramialison, M., and Poggi, L.
- (2011). Origin and Determination of Inhibitory Cell Lineages in the Vertebrate Retina. Journal of Neuroscience 31, 2549-2562
Jusuf, P.R., Almeida, A.D., Randlett, O., Joubin, K., Poggi, L., and Harris, W.A.
- (2012). Biasing Amacrine Subtypes in the Ath5 Lineage through Expression of Barhl2. Journal of Neuroscience 32, 13929-13944
Jusuf, P.R., Albadri, S., Paolini, A., Currie, P.D., Argenton, F., Higashijima, S.-i., Harris, W.A., and Poggi, L.
(See online at https://doi.org/10.1523/JNEUROSCI.2073-12.2012) - Asymmetric inheritance of the apical domain and self-renewal of
retinal ganglion cell progenitors depend on Anillin function. Development (2015) 142, 832-839
Alessio Paolini, Anne-Laure Duchemin, Shahad Albadri, Dorothee Bornhorst, Eva Patzel, Paula González Avalos, Steffen Lemke, Anja Machate, Michael Brand, Saadettin Sel, Vincenzo Di Donato, Filippo Del Bene, Flavio R. Zolessi, Mirana Ramialison and Lucia Po
(See online at https://doi.org/10.1242/dev.118612)
