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JAK/STAT pathway and Notch signaling. Inhibition of these pathways would inhibit astro- genesis and promote neurogenesis 45, and indeed, we found targeting of Notch signaling by both miR146a and miR147b, by modulation of NOTCH1. NOTCH1 targeting by miR146a was previously reported in human glioma development and neural stem cell prolifera- tion and differentiation 44. miR147b was not predicted to target NOTCH1 by prediction models, however the sequence of miR147b maps on the 3’ untranslated region (UTR) of NOTCH1 (miR147b nucleotide 1-7 maps on NOTCH1 nucleotide 52-58, and nucleotide miR147b nucleotide 3-10 maps to NOTCH1 nucleotide 569-562). miR147b also decreased JAK2, hereby also targeting the JAK/STAT pathway. This could explain why the neuro- nal fraction is even more increased in differentiated cultures transfected with miR147b mimic.
miR146a and miR147b are expressed in astrocytes in tuberous sclerosis complex and temporal lobe epilepsy
The expression and localization of miR146a has been investigated in our previous studies in TSC 17, a developmental dysregulation of cortical development, and in TLE-HS 18, in which increased expression of various inflammatory mediators, including IL-1β and glio- sis are evident 1. These studies showed that miR146a was up-regulated in epileptogenic areas where gliosis occurred, and expression was mainly found in reactive astrocytes. We investigated the expression of miR147b in TSC and TLE-HS, and in both pathologies an astrocyte-specific up-regulation of miR147b was observed, confirming the findings in fetal astrocytes after IL-1β stimulation. Expression was also found in giant cells in TSC tubers, which are involved in induction of inflammation in TSC 46. Moreover, we cannot exclude that miR147b expression could contribute to the mixed glioneuronal phenotype of these cells. The fact that the expression of miR147 was increased in two different pathologies, both associated with epilepsy, suggests that the occurrence of seizures is a critical factor. However, this needs to be further investigated. Both in control and epilep- togenic brain, miR147b was expressed in neurons, indicating possible roles in metabolism, cell growth and synaptic development. Further research would be needed in order to clarify this.
miR147b as possible therapeutic target
Recently, the potential of miR146a to inhibit inflammation in astrocytes was tested in vivo 20. In this study, miR146a mimic injections in the kainic acid mouse model of TLE inhibited IL-1R1/TLR4 signaling, resulting in arrest of epilepsy progression and an 80% reduction in spontaneous chronic seizures. This is particularly interesting, since this indicates disease modification in epilepsy using a transiently applied miRNA treatment after disease onset. Since miR147b shows a comparable expression pattern in human epileptogenic brain as well as functional effects in vitro, and even a more effective modulation of neural stem cell fate decision targeting both NOTCH1 and JAK2, it is worthwhile to investigate the effects of miR147b administration in vivo in a similar experimental setup. So far, current antiepileptic drugs provide only symptomatic control of seizures and do not modify epileptogenesis 47. Administrating miR147b may be a novel approach to modulate inflam- matory pathways underlying epileptogenic pathologies and decrease the generation of reactive astrocytes, hereby targeting mechanisms underlying disease development.