Foxg1 is an ancient transcription factor gene specifically expressed in the developing rostral brain. Here it is implicated in genetic control of multiple aspects of cerebral cortex morphogenesis, including early distinction between pallial and subpallial fields, dorsoventral patterning of the pallium, regulation of the balance between neural proliferation and differentiation, neocortical layering and tuning of astrogenesis rates. Proper Foxg1 allele dosage is crucial to normal brain morphogenesis and function. Rare microduplications of chromosome 14 fragments including Foxg1 are associated to a variant of the West Syndrome (WS), namely a devastating infantile pathological entity, characterized by seizures, abnormal interictal EEG activity, and a profound damage of cognitive abilities, persisting beyond the attenuation of EEG anomalies which often occurs around the third year of life. Aim of this thesis was to explore basic histological mechanisms possibly linking exaggerated Foxg1 expression levels by neocortical projection neurons to WS. Three were the main findings of this work. First, I found that, upon transient overexpression of Foxg1 within the pallial neuronogenic lineage, neurons originating from the engineered proliferating pool - more numerous than in controls - retain the glutamatergic phenotype and, upon transplantation into neonatal neocortex, they survive at rates comparable with wild type controls. This suggests that an increased ratio between excitatory neocortical neurons and astrocytes occurring in WS patients may jeopardize the removal of ions and metabolites released in the extracellular space upon neuronal hyperactivity. Second, I discovered that neurite overgrowth triggered by Foxg1, previously documented in vitro, takes also place in vivo, upon transplantation of engineered neurons into neonatal neocortex, regardless of neuron birthdate. Moreover, I found that the neuritic overgrowth triggered by Foxg1 was mainly restricted to dendrites. There was also an increase in axonal length and branching, however this did not reach statistical significance. Remarkably these cytoarchitectonic abnormalities may ultimately result into larger afferent basins impinging on excitatory neurons, which can ease neuronal synchronization over larger distances and contribute to EEG abnormalities of WS patients. Third, I discovered that neuronal overexpression of Foxg1 elicits a considerable increase of spines on proximal dendrites and that this effect is exacerbated upon stimulation of neuronal hyperactivity. These findings will be the starting point of an ad hoc follow-up study, aimed at unveiling molecular mechanisms which connect Foxg1 overexpression with the development of such histological anomalies. Hopefully, they will be of help for rationale design of novel therapeutic approaches aimed at alleviating and limiting the neurological damages triggered by Foxg1 duplications.
|Autori:||Do, Duc Minh|
|Titolo:||FoxG1 promotes neuritogenesis and the formation of dendritic spines - a potential mechanism for West syndrome|
|Data di pubblicazione:||30-gen-2015|
|Appare nelle tipologie:||8.1 PhD thesis|