Signs of reduced basal progenitor levels and cortical neurogenesis in human foetuses with open spina bifida at 11-15 weeks of gestation

Open spina bifida (OSB) is one of the most prevalent congenital malformations of the central nervous system that often leads to severe disabilities. Previous studies reported the volume and thickness of the neocortex to be altered in children and adolescents diagnosed with OSB. Until now, the onset and the underlying cause of the atypical neocortex organization in OSB patients remain largely unknown. To examine the effects of OSB on foetal neocortex development, we analysed human foetuses of both sexes diagnosed with OSB between 11-15 weeks of gestation by immunofluorescence for established neuronal and neural progenitor marker proteins and compared the results with healthy controls of the same, or very similar, gestational age. Our data indicate that neocortex development in OSB foetuses is altered as early as 11 weeks of gestation. We observed a marked reduction in the radial thickness of the OSB neocortex, which appears to be attributable to a massive decrease in the number of deep- and upper-layer neurons per field, and found a marked reduction in the number of basal progenitors (BPs) per field in the OSB neocortex, consistent with an impairment of cortical neurogenesis underlying the neuronal decrease in OSB foetuses. Moreover, our data suggest that the decrease in BP number in the OSB neocortex may be associated with BPs spending a lesser proportion of their cell cycle in M-phase. Together, our findings expand our understanding of the pathophysiology of OSB and support the need for an early foetal therapy, i.e. in the first trimester of pregnancy.SIGNIFICANCE STATEMENTOpen spina bifida (OSB) is one of the most prevalent congenital malformations of the central nervous system. This study provides novel data on neocortex development of human OSB foetuses. Our data indicate that neocortex development in OSB foetuses is altered as early as 11 weeks of gestation. We observed a marked reduction in the radial thickness of the OSB neocortex, which appears to be attributable a decrease in the number of deep- and upper-layer neurons per field, and found a marked reduction in the number of basal progenitors per field, indicating that impaired neurogenesis underlies the neuronal decrease in OSB foetuses. Our findings support the need for an early foetal therapy and expand our understanding of the pathophysiology of OSB.