We analysed the role of Notch signalling during the specification of the dorsal midline in Xenopus embryos. By activating or blocking the pathway we found that Notch expands the floor plate domain of sonic hedgehog and pintallavis and represses the notochordal markers chordin and brachyury, with a concomitant reduction of the notochord size. We propose that within a population of the early organiser with equivalent potential to develop either as notochord or floor plate, Notch activation favours floor plate development at the expense of the notochord, preferentially before mid gastrula. We present evidence that sonic hedgehog down-regulates chordin, suggesting that secreted Sonic hedgehog may be involved or reinforcing the cell-fate switch executed by Notch. We also show that Notch signalling requires Presenilin to modulate this switch.
Iron seems to be an essential factor in myelination and oligodendrocyte (OLGc) biology. However, the specific role of iron in these processes remains to be elucidated. Iron deficiency (ID) imposed to developing rats has been a relevant model to understand the role of iron in oligodendrogenesis and myelination. During early development ID causes specific changes in myelin composition, including a lower relative content of cholesterol, proteolipid protein (PLP), and myelin basic protein 21 (MBP21). These changes could be a consequence of the adverse effects of ID on OLGc development and function. We subsenquently studied the possible corrective effect of a single intracranial injection (ICI) of apotransferrin (aTf) on myelin formation in ID rats OLGc migration and differentiation after an ICI of aTf was evaluated at 3 days of age. ID increased the number of proliferating and undifferentiated cells in the corpus callosum (CC), while a single aTf injection reverts these effects, increasing the number of mature cells and myelin formation. Overall, results of a series of studies supports the concept that iron may affect OLGc development at early stages of embryogenesis rather than during late development. Myelin composition is altered by a limited iron supply, changes that can be reverted by a single injection of aTf.
The aim of this study was to determine whether early demyelination can impact behavior in young adulthood. For this purpose, albino Wistar rats of either sex were exposed to cuprizone (CPZ) in two different intoxication protocols: one group was intoxicated before weaning (CPZ-BW), from postnatal day 7 (P7) to P21, through maternal milk, whereas the other group was intoxicated after weaning (CPZ-AW), from P21 to P35. After treatment, rats were returned to a normal diet until P90 when behavioral studies were performed. Both treatments produced marked demyelination in the corpus callosum and retraction of cortical myelin fibers. The subsequent normal diet allowed for effective remyelination at P90. Interestingly, CPZ-AW correlated with significant behavioral and neurochemical changes in a gender-dependent manner. CPZ-AW treatment altered both the number of social activities and the latency to the first social interaction in males, while also highly compromising recognition-related activities. In addition, only P90 males treated AW showed a hyperdopaminergic striatum, confirmed by an increase in tyrosine hydroxylase expression and in dopamine levels. Our results suggest that the timing of demyelination significantly influences the development of altered behavior, particularly in adult males.
Atypical connectivity between brain regions and altered structure of the corpus callosum (CC) in imaging studies supports the long‐distance hypoconnectivity hypothesis proposed for autism spectrum disorder (ASD). The aim of this study was to unveil the CC ultrastructural and cellular changes employing the valproic acid (VPA) rat model of ASD. Male Wistar rats were exposed to VPA (450 mg/kg i.p.) or saline (control) during gestation (embryonic day 10.5), and maturation, exploration, and social behavior were subsequently tested. Myelin content, ultrastructure, and oligodendroglial lineage were studied in the CC at post‐natal days 15 (infant) and 36 (juvenile). As a functional outcome, brain metabolic activity was determined by positron emission tomography. Concomitantly with behavioral deficits in juvenile VPA rats, the CC showed reduced myelin basic protein, conserved total number of axons, reduced percentage of myelinated axons, and aberrant and less compact arrangements of myelin sheath ultrastructure. Mature oligodendrocytes decreased and oligodendrocyte precursors increased in the absence of astrogliosis or microgliosis. In medial prefrontal and somatosensory cortices of juvenile VPA rats, myelin ultrastructure and oligodendroglial lineage were preserved. VPA animals exhibited global brain hypometabolism and local hypermetabolism in brain regions relevant for ASD. In turn, the CC of infant VPA rats showed reduced myelin content but preserved oligodendroglial lineage. Our findings indicate that CC hypomyelination is established during infancy and prior to oligodendroglial pattern alterations, which suggests that axon–oligodendroglia communication could be compromised in VPA animals. Thus, CC hypomyelination may underlie white matter alterations and contribute to atypical patterns of connectivity and metabolism found in ASD.
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