Project

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Regulatory function of microRNAs in mouse retinal neurons

Applicant Krol Jacek
Number 136744
Funding scheme Ambizione
Research institution Friedrich Miescher Institute for Biomedical Research
Institution of higher education Institute Friedrich Miescher - FMI
Main discipline Molecular Biology
Start/End 01.01.2012 - 31.12.2014
Approved amount 572'010.00
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All Disciplines (3)

Discipline
Molecular Biology
Embryology, Developmental Biology
Biochemistry

Keywords (5)

retina; microRNA; noncoding RNAs; photoreceptors development; photoreceptors function

Lay Summary (English)

Lead
Visual perception requires correct assembly and function of different cell types in the retina. MicroRNAs - post-transcriptional regulators of the gene expression, have emerged as important factors controlling proper development and function of retinal neurons. The project combines integrated neurobiological and epigenetic approaches to understand complex mechanisms of the non-coding RNAs activity in photoreceptors maturation and function and in the retinal diseases.
Lay summary

Visual perception begins in the eye, where light is captured and converted into an electrochemical signals by a specialized sensory organ, the retina. These signals are then send through the optic nerve to higher centers in the brain for further processing necessary for perception. Vision requires correct development of different type of retinal neurons and their assembly into a complex regulatory network allowing proper functionality. During retinogenesis differentiation of distinct cell populations is carried out in a multi-step processes that involves cell cycle exit, migration, and changes of cell morphology. Sequential control of gene expression is necessary for the final maturation and function of specific retinal cells. Defects in the gene expression frequently results in retinal diseases or increase the susceptibility to disease.

Regulatory RNAs, like small microRNAs (miRNAs) or long non-coding RNAs (lincRNAs), are important factors controlling gene expression. Hundreds of different miRNAs have been identified in mammals. This class of RNAs is thought to repress protein synthesis by inhibiting translation of messenger RNAs and causing their destabilization. miRNAs are implicated in control of all fundamental cellular processes, including proliferation, differentiation and cell fate determination or apoptosis, and most of them are expressed in a development- or tissue-specific manner. Their role in controlling development and physiology of retinal neurons remains poorly understood.

Photoreceptor cells - rods and cones, mediate the first step in vision, capturing light and carrying out phototransduction. Our previous studies revealed that several miRNAs are predominantly expressed in mature photoreceptors and their levels are differently regulated in light and dark conditions.

The project goal is to analyze regulation of the miRNAs expression during photoreceptors development and search for potential gene targets, which controlled by miRNAs allow proper rods and cones differentiation and maturation. Investigating the mechanisms of the photoreceptors development controlled by miRNAs is of specific importance to gain a basic knowledge of how post-transcriptional regulation of the gene expression influences vision establishment and function. Finding a unique miRNAs signature for regulation of rods and cones development may help to establish new future approaches for gene therapy or for restoration of visual functions in eye diseases.

This interdisciplinary project, bringing together integrated epigenetic and neurobiology areas, will be conducted in the Friedrich Miescher Institute (FMI) in Basel, the one of the leading biomedical research centers in the Europe.  

Direct link to Lay Summary Last update: 01.02.2013

Responsible applicant and co-applicants

Employees

Publications

Publication
A network comprising short and long noncoding RNAs and RNA helicase controls mouse retina architecture.
Krol Jacek, Krol Ilona, Alvarez Claudia Patricia Patino, Fiscella Michele, Hierlemann Andreas, Roska Botond, Filipowicz Witold (2015), A network comprising short and long noncoding RNAs and RNA helicase controls mouse retina architecture., in Nature communications, 6, 7305-7305.
miRNAs 182 and 183 Are Necessary to Maintain Adult Cone Photoreceptor Outer Segments and Visual Function.
Busskamp Volker, Krol Jacek, Nelidova Dasha, Daum Janine, Szikra Tamas, Tsuda Ben, Jüttner Josephine, Farrow Karl, Scherf Brigitte Gross, Alvarez Claudia Patricia Patino, Genoud Christel, Sothilingam Vithiyanjali, Tanimoto Naoyuki, Stadler Michael, Seeliger Mathias, Stoffel Markus, Filipowicz Witold, Roska Botond (2014), miRNAs 182 and 183 Are Necessary to Maintain Adult Cone Photoreceptor Outer Segments and Visual Function., in Neuron, 83(3), 586-600.

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
European Retina Meeting Individual talk Controlled timing of miR-183/96/182 maturation by DDX3X and lncRNA leads proper photoreceptors maturation and layer organization 02.10.2013 Alicante, Spain Krol Jacek;
The 72nd Harden Conference: RNA regulators of gene expression Talk given at a conference Regulatory function of microRNAs in mouse retinal neurons 22.07.2012 Cambridge, Great Britain and Northern Ireland Krol Jacek;
The 7th Microsymposium on small RNAs Talk given at a conference Regulated processing of miR-183-182 cluster during retina developmen 21.05.2012 Basel, Switzerland , Switzerland Krol Jacek;


Associated projects

Number Title Start Funding scheme
129941 Mechanism and physiological significance of the rapid microRNA catabolism in retinal and non-retinal neurons 01.04.2010 Project funding (Div. I-III)

Abstract

MicroRNAs (miRNAs) are a large group of small noncoding RNAs encoded in genomes of a wide variety of organisms, from viruses to humans. This class of RNAs is thought to repress protein synthesis by either inhibiting translation of mRNAs or causing their destabilization. miRNAs are implicated in control of all fundamental cellular processes and most of them are expressed in a development- or tissue-specific manner. Particularly many miRNAs are specifically expressed or enriched in neuronal cells, including retinal neurons, consistent with a growing evidence of importance of miRNAs for brain development and function. In neurons miRNAs are implicated in the regulation of translation at dendritic spines in response to synaptic stimulation.The mammalian retina consists of three neuronal cell body and two synaptic layers representing a complex network of many different cell types. It is an excellent system to study formation of neuronal circuits in development and the regulation of gene expression in response to different intrinsic and extrinsic factors. We have recently identified miRNAs which are reversibly up and down regulated in vivo in the mouse retina during dark-light adaptation, independent of the circadian rhythm. Sensory neuron-specific miR-183/96/182 cluster and few other miRNAs were down-regulated during dark adaptation and up-regulated in light, with rapid miRNA decay and increased transcription being responsible for the changes. We found that miRNAs in retinal neurons, both light-regulated and constitutively expressed, turn over much faster than miRNAs in non-neuronal cells. We further demonstrated that the fast turnover of miRNAs is also characteristic of hippocampal and cortical neurons, and neurons differentiated from mouse embryonic stem (ES) cells in vitro. Importantly, blocking action potentials with tetrodotoxin or the glutamate receptors with specific antagonists reduced miRNA turnover, indicating that active miRNA metabolism may be important for the function of neurons. These results indicated that a link exists between neuronal activity and turnover of miRNAs. During retinogenesis, differentiation of distinct cell populations in retina is carried out in a multi-step processes that involves cell cycle exit, migration, and changes of cell morphology. Sequential control of gene expression is necessary for the final maturation and function of specific retinal cells. Photoreceptors mediate the first step in vision, capturing light and carrying out phototransduction. The miR-183/96/182 cluster miRNAs are predominantly expressed in mature photoreceptors, however their role in development of rods and cones remains unknown. In the proposed project, I intend to study regulation of the miR-183/96/182 cluster expression during photoreceptors development and to identify potential gene targets which, through regulation by the miR-183/96/182, allow proper rods and cones cell-fate commitment. Investigating the mechanisms of the photoreceptors development controlled by miRNAs is of specific importance to gain a basic knowledge of how post-transcriptional regulation of the gene expression influencing vision establishment. Finding a unique miRNAs signature for regulation of rods and cones development may help to establish new future approaches for gene therapy or for restoration of visual functions in eye diseases.Details of miRNA biogenesis and its regulation are quite well established, however little is known about the regulation and the role of the mature miRNAs catabolism. miRNAs are generally assumed to have a very long half-life, corresponding to many hours or even days. However, such slow turnover is not a universal feature of miRNAs since, as already discussed above, we have found that miRNAs turn over rapidly in retinal and non-retinal neurons. In the second part of the proposed research, I intend to gain some insight into the physiological role of activity-regulated miRNA turnover in neurons. Looking into the kinetics of miRNAs decay in different compartments of neuronal cell or different type of neurons subjected to various physiological and pharmacological conditions, I would like to enrich understanding of how miRNAs regulates neuronal function.
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