Abstract
Neuropathological diseases of the central nervous system (CNS) are frequently associated with impaired differentiation of the oligodendroglial cell lineage and subsequent alterations in white matter structure and dynamics. Down syndrome (DS), or trisomy 21, is the most common genetic cause for cognitive impairments and intellectual disability (ID) and is associated with a reduction in the number of neurons and oligodendrocytes, as well as with hypomyelination and astrogliosis. Recent studies mainly focused on neuronal development in DS and underestimated the role of glial cells as pathogenic players. This also relates to C21ORF91, a protein considered a key modulator of aberrant CNS development in DS. We investigated the role of C21orf91 ortholog in terms of oligodendrogenesis and myelination using database information as well as through cultured primary oligodendroglial precursor cells (OPCs). Upon modulation of C21orf91 gene expression, we found this factor to be important for accurate oligodendroglial differentiation, influencing their capacity to mature and to myelinate axons. Interestingly, C21orf91 overexpression initiates a cell population coexpressing astroglial- and oligodendroglial markers indicating that elevated C21orf91 expression levels induce a gliogenic shift towards the astrocytic lineage reflecting non-equilibrated glial cell populations in DS brains.
Highlights
White matter, which makes up approximately 40% of the human brain, consists of axons, astrocytes, and myelin, the latter of which is imperative for stabilization, protection, and electrical insulation of axons enabling accelerated electrical signal propagation
The other coexpressed genes are phospholipidase D1 (PLD1), which promotes dendritic spine morphogenesis via polycystic kidney disease 1/polycystin 1 (PKD1) activation (Li et al, 2019), RFFL which is reported to be expressed in the corpus callosum, brain stem, spinal cord and cerebellar white matter, and heat shock protein family A member 2 (HSPA2) and proline rich 5 like (PRR5L), for which we did not find evidence for function in nervous system processes, oligodendrogenesis or myelination
The C21ORF91 gene has so far not been investigated in the context of oligodendrogenesis and white matter, it was listed within the dysregulated gene network M43 in Down syndrome (DS) which is associated with oligodendroglial development and myelination (Olmos-Serrano et al, 2016)
Summary
White matter, which makes up approximately 40% of the human brain, consists of axons, astrocytes, and myelin, the latter of which is imperative for stabilization, protection, and electrical insulation of axons enabling accelerated electrical signal propagation. The structural integrity of myelin is of crucial importance for CNS function and restoration (Snaidero and Simons, 2014), making it vulnerable to pathological degeneration and inflammation (Waxman, 1992) or genetic intervention (Nave, 1994). Leads to impaired neuronal signaling, functional deficits, and shortened lifetime (Wilkins et al, 2003). White matter deficits and myelin dysfunctions are considered a main contributing factor for neurodegenerative diseases and malfunctions of the CNS (Bercury and Macklin, 2015)
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