Involvement of stat3 in mouse brain development and sexual dimorphism: A proteomics approach

Fabio Di Domenico, Gabriella Casalena, Rukhsana Sultana, Jian Cai, William M. Pierce, Marzia Perluigi, Chiara Cini, Alessandra Baracca, Giancarlo Solaini, Giorgio Lenaz, Jia Jia, Suzan Dziennis, Stephanie J. Murphy, Nabil J. Alkayed, D. Allan Butterfield

Research output: Contribution to journalArticlepeer-review

17 Scopus citations

Abstract

Although the role of STAT3 in cell physiology and tissue development has been largely investigated, its involvement in the development and maintenance of nervous tissue and in the mechanisms of neuroprotection is not yet known. The potentially wide range of STAT3 activities raises the question of tissue- and gender-specificity as putative mechanisms of regulation. To explore the function of STAT3 in the brain and the hypothesis of a gender-linked modulation of STAT3, we analyzed a neuron-specific STAT3 knockout mouse model investigating the influence of STAT3 activity in brain protein expression pattern in both males and females in the absence of neurological insult. We performed a proteomic study aimed to reveal the molecular pathways directly or indirectly controlled by STAT3 underscoring its role in brain development and maintenance. We identified several proteins, belonging to different neuronal pathways such as energy metabolism or synaptic transmission, controlled by STAT3 that confirm its crucial role in brain development and maintenance. Moreover, we investigated the different processes that could contribute to the sexual dimorphic behavior observed in the incidence of neurological and mental disease. Interestingly both STAT3 KO and gender factors influence the expression of several mitochondrial proteins conferring to mitochondrial activity high importance in the regulation of brain physiology and conceivable relevance as therapeutic target.

Original languageEnglish
Pages (from-to)1-12
Number of pages12
JournalBrain Research
Volume1362
DOIs
StatePublished - Nov 29 2010

Bibliographical note

Funding Information:
The hypothesis of an unstable equilibrium redox in males STAT3 KO is supported by the decreased expression of Prdx6. HDH is a mitochondrial membrane enzyme involved in the NAD-dependent metabolism of ketone bodies. Our data showed that in STAT3 KO male brain the expression of both PDH and HDH is severely down regulated, thus leading to a condition in which mitochondria could be deprived of substrates for TCA cycle. Therefore, in males the knock out of STAT3 gene likely results in a deficit in the mitochondrial capacity to adapt to changes in substrates availability, which could make them more vulnerable upon stress inducing events.

Keywords

  • Neuron-Specific STAT3
  • Proteomics
  • Sexual dimorphism

ASJC Scopus subject areas

  • General Neuroscience
  • Molecular Biology
  • Clinical Neurology
  • Developmental Biology

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