Premature Neural Progenitor Cell Differentiation Into Astrocytes in Retinoic Acid-Induced Spina Bifida Rat Model

Abstract

During embryonic spinal cord development, neural progenitor cells (NPCs) generate three major cell lines: neurons, oligodendrocytes, and astrocytes at precise times and locations within the spinal cord. Recent studies demonstrate early astrogenesis in animal models of spina bifida, which may play a role in neuronal dysfunction associated with this condition. However, to date, the pathophysiological mechanisms related to this early astrocytic response in spina bifida are poorly understood. This study aimed to characterize the development of early astrogliosis over time from Pax6+, Olig2+, or Nkx2.2+ NPCs using a retinoic acid-induced spina bifida rat model. At three gestational ages (E15, E17, and E20), spinal cords from fetuses with retinoic acid-induced spina bifida, their healthy sibling controls, or fetuses treated with the vehicle control were analyzed. Results indicated that premature astrogliosis and astrocytic activation were associated with an altered presence of Pax6+, Olig2+, and Nkx2.2+ NPCs in the lesion compared to the controls. Finally, this response correlated with an elevation in genes involved in the Notch-BMP signaling pathway. Taken together, changes in NPC patterning factor expression with Notch-BMP signaling upregulation may be responsible for the altered astrogenesis patterns observed in the spinal cord in a retinoic acid-induced spina bifida model.

AQP4, Astrogenesis, and Hydrocephalus: A New Neurological Perspective

“…The GSCs’ early differentiation into reactive astrocytes could be considered a complementary neurodevelopmental disorder since the GSCs lose their projection, and the glioblasts are no longer migrating toward the white matter tracks. A similar mechanism of premature progenitor differentiation into astrocytes has been recently confirmed in a rat model with spina bifida [ 73 ]. This early differentiation into astrocytes could explain the characteristic white matter alterations found in pediatric hydrocephalus [ 74 , 75 , 76 ].…”

Astrocytes in human central nervous system diseases: a frontier for new therapies

“…In particular, spina bifida is characterised by premature astrogliogenesis, which affects neuronal development and instigates reactive astrogliosis. 482 Astrocytic RASopathy Mutations of rat sarcoma virus or RAS proteins are behind a class of disorders known as RASopathies. 483 Frequently, RASopathies present cognitive deficits and delayed cognitive development.…”

Development of a Single-Neurosphere Culture to Assess Radiation Toxicity and Pre-Clinical Cancer Combination Therapy Safety

“…NPC differentiation is dependent on bone morphogenetic proteins (BMPs) [29,30]. These morphogens are key regulators of NPC differentiation potential toward neuron and glia cell lineages [31,32] and are upregulated in NPCs following insult or disease [33]. In addition, the BMP signaling pathway has been proven to regulate astrocyte commitment in the CNS [34,35].…”