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The evolution of multicellularity occurred hand in hand with the diversification of cell types with disparate morphologies and functions. This segregation of function across different cell types enabled astounding animal complexity; but at the same time, extreme specializations of individual cell types often leave them vulnerable to genetic or environmental variations (e.g. the highly specialized physiology of some neurons or muscle cells makes them particularly susceptible to mutations in broadly expressed genes, that do not affect other cell types). Therefore, understanding how cells diversify and what makes them unique, is important to understand animal physiology in health and disease. Our work has explored two aspects of animal cell diversification, with a focus on the gene-regulatory mechanisms that underlie this process.
First, we ask how different cell types are specified along the developmental process. Specifically, we have focused on neurons and muscle cells that follow different trajectories but later seemingly converge to the same terminal identity. Developmental convergence is widespread in animal development, and we have established models and tools to study the gene-regulatory mechanisms behind two aspects of this phenomenon: i) how do cells from different lineages converge to the same terminal identity, and ii) do convergent cell types carry molecular and functional signatures of their different histories.
Second, we explore what defines the unique properties of specialized cells. Post-transcriptional repression by miRNAs contributes to cell specialization, and we focus on the roles of miRNAs in neuron and muscle diversification. Moreover, we found that miRNAs support the unique physiology of some specialized cells by selective repression of otherwise broadly-transcribed, house-keeping genes. Such reduced house- keeping function represents a possible source of susceptibilities in specialized cells, which we have been following up in the context of neurons and muscle cells.
To address these questions, we draw from the molecular biology, genetics and RNA biochemistry toolsets, also developing novel, necessary tools ourselves (e.g. a method to sequence miRNAs from individual cell types within complex tissues, see more below). To extract fundamental concepts in cellular differentiation, we use the nematode C. elegans as our primary model system. This is mainly because it allows us to design experiments with unparalleled cellular resolution, but also because the vast body of work amassed by the community working on this animal provides a superb background enabling deep mechanistic understanding. At the same time, the mechanisms that we study are basic molecular mechanisms that also operate in other vertebrates and invertebrates.
Gutiérrez-Pérez P, Santillán EM, Lendl T, Schrempf A, Steinacker TL, Asparuhova M, Brandstetter M, Haselbach D and Cochella L. miR-1 sustains muscle physiology by controlling V-ATPase complex assembly. In press at Sci. Advances. Previously on bioRxiv: https://doi.org/10.1101/2020.08.31.275644
Özkan E, Strobl MM, Novatchkova M, Yelagandula R, Albanese TG, Triska P, Endler L, Penz T, Patocka T, Felsenstein V, Vogt A, Tamir I, Seitz T, Födinger M,Herwig R, Indra A, Schmid D, Bock C, Bergthaler A, Stark A, Allerberger F, Elling U*, Cochella L.* High-throughput Mutational Surveillance of the SARS-CoV-2 Spike Gene. medRxiv 2021.07.22.21259587; doi: https://doi.org/10.1101/2021.07.22.21259587. *co-corresponding, equal contribution
Yelagandula R, Bykov A, Vogt A, Heinen R, Özkan E, Strobl MM, Baar JC, Uzunova K, Hajdusits B, Kordic D, Suljic E, Kurtovic-Kozaric A, Izetbegovic S, Schaeffer J, Hufnagl P, Zoufaly A, Seitz T; VCDI, F√∂dinger M, Allerberger F, Stark A, Cochella L*, Elling U*. Multiplexed detection of SARS-CoV-2 and other respiratory infections in high throughput by SARSeq. Nat Commun. 2021 May 25;12(1):3132. doi: 10.1038/s41467-021-22664-5. PMID: 34035246; PMCID:PMC8149640. *co-corresponding, equal contribution
Ketting RF, Cochella L. Concepts and functions of small RNA pathways in C. elegans. Curr Top Dev Biol. 2021;144:45-89. doi: 10.1016/bs.ctdb.2020.08.002. Epub 2020 Oct 3. PMID: 33992161. [Book chapter]
Dexheimer PJ, Wang J, Cochella L. Two MicroRNAs Are Sufficient for Embryonic Patterning in C. elegans. Curr Biol. 2020 Dec 21;30(24):5058-5065.e5. doi:10.1016/j.cub.2020.09.066. Epub 2020 Oct 29. PMID: 33125867; PMCID: PMC7758728.
Charest J, Daniele T, Wang J, Bykov A, Mandlbauer A, Asparuhova M, Röhsner J, Gutiérrez-Pérez P, Cochella L. Combinatorial Action of Temporally Segregated Transcription Factors. Dev Cell. 2020 Nov 23;55(4):483-499.e7. doi: 10.1016/j.devcel.2020.09.002. Epub 2020 Sep 30. PMID: 33002421; PMCID: PMC7704111.
Dexheimer PJ, Cochella L. MicroRNAs: From Mechanism to Organism. Front Cell Dev Biol. 2020 Jun 3;8:409. doi: 10.3389/fcell.2020.00409. PMID: 32582699; PMCID: PMC7283388. [Review]
Alberti C, Manzenreither RA, Sowemimo I, Burkard TR, Wang J, Mahofsky K, Ameres SL*, Cochella L*. Cell-type specific sequencing of microRNAs from complex animal tissues. Nat Methods. 2018 Apr;15(4):283-289. doi: 10.1038/nmeth.4610. Epub 2018 Feb 26. PMID: 29481550; PMCID: PMC5886366. *co-corresponding
Alberti C, Cochella L. A framework for understanding the roles of miRNAs in animal development. Development. 2017 Jul 15;144(14):2548-2559. doi: 10.1242/dev.146613. PMID: 28720652. [Review]
Drexel T, Mahofsky K, Latham R, Zimmer M, Cochella L. Neuron type-specific miRNA represses two broadly expressed genes to modulate an avoidance behavior in C. elegans. Genes Dev. 2016 Sep 15;30(18):2042-2047. doi: 10.1101/gad.287904.116. Epub 2016 Sep 29. PMID: 27688400; PMCID: PMC5066611.