Signal Transducer Activator of Transcription 3 (STAT3) is a relevant transcription factor in numerous biological contexts, including the immune system, neoplasm formation and bone tissue homeostasis. In particular, loss-of-function mutations (LOF) affecting STAT3 cause bone development defects, which include skeletal abnormalities and reduced bone density. Danio rerio (zebrafish) was used as a model organism to investigate the role of STAT3 in bone tissue in vivo. More specifically, two zebrafish mutant lines were generated: one line in which the stat3 gene was completely knocked out (KO) and one line in which gene manipulation truncated the transactivation domain (ΔTAD), preventing the protein’s canonical activation. The results obtained show that stat3-/- mutants have reduced growth, skeletal defects and early mortality, but no defects in cartilage formation. In addition, following tail damage, stat3-/- mutants show a considerable reduction of bone regeneration, correlated with low infiltration of macrophages and neutrophils. The stat3ΔTAD line, on the other hand, shows only partially the same phenotypes, indicating the potential presence of non-canonical activities of Stat3.
La proteina Signal Transducer Activator of Transcription 3 (STAT3) è un fattore di trascrizione rilevante in numerosi contesti biologici, tra cui il sistema immunitario, la formazione di neoplasie e l’omeostasi del tessuto osseo. In particolare, mutazioni loss-of-function (LOF) a suo carico provocano difetti dello sviluppo osseo che includono anomalie scheletriche e una ridotta densità ossea. Per indagare il ruolo di STAT3 nel tessuto osseo in vivo, è stato utilizzato Danio rerio (zebrafish) come organismo modello. Più nel dettaglio, sono state generate due linee mutanti di zebrafish: una linea in cui il gene stat3 ha subito un knock out completo (KO) e una linea in cui la manipolazione genica ha troncato il dominio di transattivazione (ΔTAD), impedendo l’attivazione canonica della proteina. I risultati ottenuti mostrano che i mutanti stat3-/- hanno una crescita ridotta, difetti scheletrici e mortalità precoce, tuttavia non presentano difetti nella formazione della cartilagine. Inoltre, a seguito di un danno alla coda, i mutanti stat3-/- mostrano una riduzione considerevole della rigenerazione ossea, correlata ad una scarsa infiltrazione di macrofagi e neutrofili. La linea stat3ΔTAD invece mostra solo parzialmente gli stessi fenotipi, indicando la potenziale presenza di attività non canoniche di Stat3.
Il ruolo di STAT3 nello sviluppo del tessuto osseo e nella sua rigenerazione
LAZZARIN, SOFIA
2023/2024
Abstract
Signal Transducer Activator of Transcription 3 (STAT3) is a relevant transcription factor in numerous biological contexts, including the immune system, neoplasm formation and bone tissue homeostasis. In particular, loss-of-function mutations (LOF) affecting STAT3 cause bone development defects, which include skeletal abnormalities and reduced bone density. Danio rerio (zebrafish) was used as a model organism to investigate the role of STAT3 in bone tissue in vivo. More specifically, two zebrafish mutant lines were generated: one line in which the stat3 gene was completely knocked out (KO) and one line in which gene manipulation truncated the transactivation domain (ΔTAD), preventing the protein’s canonical activation. The results obtained show that stat3-/- mutants have reduced growth, skeletal defects and early mortality, but no defects in cartilage formation. In addition, following tail damage, stat3-/- mutants show a considerable reduction of bone regeneration, correlated with low infiltration of macrophages and neutrophils. The stat3ΔTAD line, on the other hand, shows only partially the same phenotypes, indicating the potential presence of non-canonical activities of Stat3.File | Dimensione | Formato | |
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https://hdl.handle.net/20.500.12608/70602