Gangliosides in Nerve Cell Specification

Abstract

The central nervous system is generated from progenitor cells that are recognized as neural stem cells (NSCs). NSCs are defined as undifferentiated neural cells that are characterized by the capacity for self-renewal and multipotency. Throughout neural development, NSCs undergo proliferation, migration, and cellular differentiation, and dynamic changes are observed in the composition of carbohydrate-rich molecules, including gangliosides. Gangliosides are sialic acid-containing glycosphingolipids with essential and multifaceted functions in brain development and NSC maintenance, which reflects the complexity of brain development. Our group has pioneered research on the importance of gangliosides for growth factor receptor signaling and epigenetic regulation of ganglioside biosynthesis in NSCs. We found that GD3 is the predominant ganglioside species in NSCs (>80%) and modulates NSC proliferation by interacting with epidermal growth factor receptor signaling. In postnatal brain, GD3 is required for long-term maintenance of NSCs. Deficiency in GD3 leads to developmental and behavioral deficits, such as depression. The synthesis of GD3 is switched to the synthesis of complex, brain-type gangliosides, namely, GM1, GD1a, GD1b, and GT1b, resulting in terminal differentiation and loss of “stemness” of NSCs. In this process, GM1 is augmented by a novel GM1-modulated epigenetic gene regulation mechanism of glycosyltransferases at a later differentiation stage. Consequently, our research suggests that stage-specific gangliosides play specific roles in maintaining NSC activities and in cell fate determination.

Gangliosides in the Brain: Physiology, Pathophysiology and Therapeutic Applications

“…Expression of ganglioside biosynthetic enzymes and production of specific gangliosides are developmentally regulated processes ( Yanagisawa and Yu, 2007 ; Itokazu et al, 2018 ). At early developmental stages, in the rodent brain, the ganglioside profile is dominated by simple gangliosides (GM3 and GD3).…”

“…At early developmental stages, in the rodent brain, the ganglioside profile is dominated by simple gangliosides (GM3 and GD3). GD3 is the predominant ganglioside expressed on the surface of neural stem cells (NSC) where its interaction with the EGFR ensures receptor recycling after endocytosis and maintenance of self-renewal capacity ( Itokazu et al, 2018 ). NSC differentiation to neuronal progenitors is accompanied by a shift from the synthesis of GD3 to GM1, which was proposed to promote expression of neuronal-specific genes ( Itokazu et al, 2017 ).…”

Gangliosides and Neuroblastomas

“…In addition to noting the varied effects gangliosides induce via signal transduction, investigators studying neural differentiation are tracing those pathways to identify their effects on transcription (e.g., [ 90 , 91 , 92 , 97 , 98 ]). A more direct effect of a ganglioside on transcription was provided by the observation that GM1 associated with the nuclear lamina of differentiated neurons could bind to acetylated histones on the promoters of Galnt and Neurod1 to influence their activity [ 99 ].…”

Human Sialic acid O-acetyl esterase (SIAE) – mediated changes in sensitivity to etoposide in a medulloblastoma cell line

“…One of the most characterized gangliosides in the brain is GD3 12–14 . GD3 is a predominant ganglioside in neural stem cells, where it has been shown to play a role in proliferation via epidermal growth factor receptor signaling 15 . GD3 and its acetylated form GD3 A are both known to be expressed by granule neuron precursors (GPCs) during cerebellar development 16 , and these cells are implicated in the pathology of SHH MB 17 .…”