Modulation of fibronectin expression in astrocytes affects neuritogenesis: Relevance in developmental neurotoxicity

Lucio G. Costa, Marina Guizzetti, Daniella Pizzurro, Gennaro Giordano

Research output: Chapter in Book/Report/Conference proceedingChapter

1 Scopus citations


Neurite outgrowth in CNS neurons is primarily dependent on extracellular matrix proteins that are produced and released by glial cells. One of these proteins, fibronectin, together with laminin, plays a pivotal role in neuronal differentiation mediated by astrocytes. When co-cultured together, astrocytes interact with neurons and promote their differentiation; interference with this interaction can indirectly affect neuronal development. Cholinergic agonists, through activation of muscarinic M3 receptors in astrocytes increase their ability to promote neuritogenesis, largely by increasing the expression and release of fibronectin and laminin. This effect is mediated by activation of multiple signal transduction pathways in astrocytes. Ethanol, a known developmental neurotoxicant, inhibits muscarinic receptor signal transduction at the level of phosphor-lipase D, and antagonizes the astrocyte-mediated neuritogenic effect on hippocampal neurons. Similar effects of muscarinic agonists and of ethanol have been also seen in the in vitro hippocampal slice. Thyroid hormones (T3) can increase fibronectin expression in astrocytes, and hence increase neuritogenesis in cerebellar neurons. Conversely, astrocytes from hypothyroid animals, a condition know to cause profound developmental neurotoxicity, have decreased levels of fibronectin and decreased ability to promote neuritogenesis. The metal manganese, also increasingly recognized as a developmental neurotoxicant, accumulates in astrocytes, where it causes oxidative stress. Upon exposure to manganese, astrocytes have a decreased expression /release of fibronectin, and a decreased ability to foster neuritogenesis in hippocampal neurons. These effects are due to manganese-induced oxidative stress and are antagonized by antioxidants. Other oxidants, such as hydrogen peroxide or 2,3-dimethoxy-1,4-naphtoquinone, cause similar effects on astrocytic fibronectin and on neuritogenesis. Additionally, certain organophosphorus insecticides, such as diazinon and its oxygen analog diazoxon, which can also cause oxidative stress, are also capable of altering fibronectin expression and neuritogenesis. These studies indicate that interference with fibronectin expression/release in astrocytes greatly affects their ability to exert neuritogenic effects on developing neurons.

Original languageEnglish (US)
Title of host publicationFibronectin
Subtitle of host publicationCurrent Concepts in Structure, Function and Pathology
PublisherNova Science Publishers, Inc.
Number of pages13
ISBN (Print)9781622572984
StatePublished - 2012
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)


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