Myelination and motor coordination are increased in transferrin transgenic mice

Abstract

Myelin deficiency in the central nervous system (CNS) can cause severe disabling conditions. Most of the transgenic mice models overexpressing myelin components have limitations for investigators of myelin deficiency and myelin therapy as they severely alter CNS architecture. It has been postulated that transferrin (Tf) is involved in oligodendrocyte (OL) maturation and myelinogenesis. Because Tf is not an intrinsic myelin constituent, we decided to investigate if its overexpression could have an impact on the myelination process without affecting myelin integrity. We generated transgenic mice containing the complete human Tf gene specifically overexpressed in OLs. This overexpression leads to more than a 30% increase in myelin components, such as galactolipids, phospholipids, and proteins. Electron microscopy showed that myelin is structurally normal in terms of thickness and compaction. Behavior analysis showed that mice do not display significant modifications in their locomotion and cognitive and emotional abilities. Furthermore, in one of the genetic background, animals presented a significant increase in motor coordination. We did not find any modification in OL number during early postnatal development, suggesting that Tf does not act on OL proliferation. In addition, the levels of iron and ferritin remained unchanged in the brain of transgenic mice compared to control mice. Our findings indicate that, besides its known iron transport function, Tf is able to influence myelination process and induce behavioral improvements in mice.

Expression of transcripts for myelination-related genes in the anterior cingulate cortex in schizophrenia☆

“…This result is consistent with microarray and QPCR findings of decreased TF mRNA expression in DLPFC samples containing both gray and white matter in schizophrenia, and is further supported by six positive linkage studies for the TF gene in schizophrenia (Hakak et al, 2001;Davis et al, 2003;Tkachev et al, 2003). Several preclinical studies have demonstrated a critical role for TF in myelination and oligodendrocyte maturation (Espinosa de los Monteros et al, 1999;Saleh et al, 2003). TF is an iron transport glycoprotein synthesized in the liver by hepatocytes, by distinct types of well-differentiated epithelial cells, and by oligodendrocytes and the choroid plexus in the CNS (Skinner and Griswold, 1980;Bloch et al, 1985;Bloch et al, 1987;Lee et al, 1987;Tu et al, 1991).…”

“…TF made by oligodendrocytes is functionally distinct from TF synthesized by other tissues, likely secondary to alternative splicing (de Arriba Zerpa et al, 2000;Duchange et al, 2002). TF expression correlates with the synthesis of myelin and the normal development of oligodendrocytes in rodent models, and the replacement of TF with exogenous apo-transferrin restores myelination in P5 rat pups (Bartlett et al, 1991;Connor et al, 1993;Saleh et al, 2003). Thus, a decrease in TF expression is consistent with the hypothesis that synthesis and maintenance of myelin is disrupted in schizophrenia.…”

Inhalation of growth factors and apo-transferrin to protect and repair the hypoxic-ischemic brain

“…This promyelinating effect was also seen in primary cultures of oligodendrocytes [34], as well as in oligodendroglial cell lines treated with aTf [35,36]. We have demonstrated that aTf modulates the expression of myelin basic protein (MBP) through different signaling pathways and, furthermore, we have shown that aTf overexpression promotes oligodendrocyte differentiation and myelination of cortical neurons [36,37].These data have been confirmed by other authors who showed that aTf regulates MBP expression [38] and that transgenic mice overexpressing the human Tf gene in the CNS evidence increased myelination [39].…”

Sensitivity and specificity of decreased CSF asialotransferrin for eIF2B-related disorder

“…Of note, an increase in CSF asialotransferrin to transferrin ratio has been reported in patients with congenital disorders of glycosylation since these disorders have been recognized. 30 There is increasing evidence that transferrin plays a role in oligodendrocyte maturation and homeostasis, [31][32][33][34][35][36][37] in addition to its known role in iron metabolism and oxidative stress. 38 Thus, decreased asialotransferrin to transferrin ratio in the CSF may simply be a manifestation of disturbed protein homeostasis within the CNS as a result of EIF2B mutations, or it may play a role in the pathophysiology of the disorder.…”