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Peron, Margherita (2017) Stat3-dependent mitochondrial DNA transcription drives stem cells proliferation in zebrafish. [Ph.D. thesis]

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Abstract (english)

The Signal Transducer and Activator of Transcription 3 (STAT3) is a transcription factor known to be involved in a plethora of physiological processes such as development, differentiation, immunity and metabolism, thus leading to transcription of anti-apoptotic, pro-proliferative and immune response target genes. Importantly, STAT3 pathway was also found aberrantly active in many human pathological conditions including 70% of solid and haematological tumours.
With the aim to investigate the putative role of Stat3 in vivo in physiological and pathological conditions, we generated and validated a transgenic line reporting the spatial and temporal expression pattern of canonical Stat3 pathway in zebrafish. It expresses a stabilized form of GFP fluorescent protein under the control of 7 multimerized STAT3 responsive elements from the promoter of the human STAT3 target gene CRP. The characterization of the reporter fluorescent pattern revealed that Stat3 activity is inherited maternally from the oocyte, and that the pathway is active during early developmental stages, in particular in the developing nervous system (telencephalon, optic tectum and hindbrain) from 20 hpf and in the intestine from 4 dpf until adulthood. In these tissues, Stat3 pathway is active in a restricted population of proliferating cells, in which, the chemical inhibition of Stat3 activity results in a significant reduction of the mitotic rate, suggesting that cell division is Stat3-dependent. In particular, in the intestinal epithelium of zebrafish larvae, Stat3 chemical ablation causes the depletion of intestinal folds formation, assessing Stat3 to be necessary for normal intestinal development. The generation of a novel stat3-KO mutant fish by Crispr-Cas9 mutagenesis confirmed the absolute requirement of Stat3 transcription factor for the formation of physiologic intestinal mucosa. In the adult zebrafish, Stat3 activity in the intestine is limited to the Crypt Base Columnar cells, a population of adult stem cells that is actively proliferating in order to sustain intestinal cells turnover. Moreover, in the zebrafish apc- genetic model for human colorectal cancer, Stat3 reporter activity is much increased in the intestinal adenomatous polyps, where it possibly marks the tumour initiating cancer stem cells, thus suggesting Stat3 to be a marker of stemness in the zebrafish.
According to some recent data collected in vitro, a limited pool of Stat3 localize to mitochondria, where it acts as a mitochondrial transcription factor inducing proliferation and maintaining pluripotency in ESC. In this work we provide in vivo evidences that mitoStat3 positively regulates embryonic proliferation through expression of mitochondrial genes, and that in zebrafish, mitoStat3 transcriptional activity depends on both Y705 and S727 phosphorylation.
In its entirety, our work supports the idea that Stat3 regulates stem cells proliferation through mitochondrial genes expression in zebrafish.

Abstract (italian)

Il fattore trascrizionale STAT3 (Signal Transducer and Activator of Transcription 3), è noto per essere coinvolto in una varietà di processi fisiologici tra i quali lo sviluppo, il differenziamento cellulare, l’immunità e il metabolismo, attraverso la regolazione dell’espressione di geni target anti-apoptotici, pro-proliferativi e coinvolti nei meccanismi di risposta immunitaria. Inoltre, è stata osservata l’attivazione ectopica della via di segnale STAT3 in numerose patologie umane che includono il 70% dei tumori sia solidi che ematologici.
Con lo scopo di studiare in vivo il ruolo di Stat3 sia in condizioni fisiologiche che nel processo di patogenesi, è stata generata una linea transgenica biosensore della via canonica di segnale Stat3, in grado di riportarne l’attivazione spaziale e temporale nell’organismo modello zebrafish.
Essa esprime la proteina fluorescente verde EGFP sotto il controllo di 7 elementi ripetuti in tandem contenenti le sequenze responsive a Stat3; tali elementi, sono stati ottenuti dal promotore del gene CRP di uomo, un noto bersaglio dell’attività trascrizionale di Stat3.
La caratterizzazione del segnale fluorescente del pesce reporter ha dimostrato che la proteina Stat3 manifesta effetto materno, essendo ereditata dallo zigote a partire dall’oocita della madre; inoltre, la via di segnale è attiva durante le prime fasi dello sviluppo di zebrafish, in particolare nel sistema nervoso (telencefalo, tetto ottico e cervello posteriore) dalle 20 ore dopo la fecondazione, e nell’intestino a partire dai 4 giorni fino all’età adulta. In entrambi questi tessuti il segnale reporter marca cellule proliferanti, che a seguito della somministrazione di inibitori chimici della via di segnale Stat3 riducono significativamente la loro attività mitotica, suggerendo che il processo di divisione cellulare dipende da Stat3 durante lo sviluppo di zebrafish. In particolare nell’epitelio intestinale delle larve, l’inibizione chimica della via di segnale Stat3 causa difetti nella formazione dei villi intestinali, rivelando che Stat3 è necessario per il corretto sviluppo dell’epitelio intestinale in zebrafish. Tale risultato è stato avvalorato a seguito della creazione di un mutante KO per il gene stat3, il quale ha confermato l’assoluta necessità della proteina Stat3 per la formazione della normale mucosa intestinale. Nell’intestino di zebrafish adulti l’attività della via di segnale Stat3 è limitata ad una ristretta popolazione di cellule staminali adulte localizzate alla base della cripta, che proliferano attivamente per garantire il ricambio cellulare tipico di questo tessuto.
Inoltre, nello zebrafish modello per il tumore colon-rettale umano, caratterizzato da una mutazione al gene apc, l’attività della via di segnale Stat3 riportata dal pesce reporter è significativamente maggiore nei polipi adenomatosi, dove verosimilmente è attiva nelle cellule staminali tumorali iniziatrici del cancro; tali risultati suggeriscono per Stat3 un ruolo come marcatore di staminalità in zebrafish.
Secondo alcune recenti pubblicazioni basate su dati ottenuti in vitro, una quantità limitata di proteina STAT3 è stata localizzata nel mitocondrio, dove agisce come fattore trascrizionale mitocondriale, inducendo la proliferazione e mantenendo la pluripotenza delle cellule staminali embrionali di topo. In questo lavoro vengono presentati dati ottenuti in vivo, a dimostrazione che mitoStat3 regola positivamente il processo proliferativo attraverso l’espressione di geni mitocondriali; si è inoltre dimostrato che l’attività trascrizionale di mitoStat3 dipende dalla fosforilazione ad entrambi gli amminoacidi Y705 e S727.
Nel suo complesso il nostro lavoro dimostra che il fattore trascrizionale Stat3 è in grado di regolare la proliferazione nelle cellule staminali attraverso l’espressione di geni mitocondriali in zebrafish.

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EPrint type:Ph.D. thesis
Tutor:Argenton, Francesco
Ph.D. course:Ciclo 29 > Corsi 29 > BIOSCIENZE E BIOTECNOLOGIE
Data di deposito della tesi:30 January 2017
Anno di Pubblicazione:30 January 2017
Key Words:Stat3, zebrafish, proliferation
Settori scientifico-disciplinari MIUR:Area 05 - Scienze biologiche > BIO/13 Biologia applicata
Struttura di riferimento:Dipartimenti > Dipartimento di Biologia
Codice ID:10082
Depositato il:24 Nov 2017 09:43
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