Abstract
Oligodendrocyte precursor cells (OPC), neurons and astrocytes share a neural progenitor cell (NPC) in the early ventricular zone (VZ) of the embryonic neuroepithelium. Both switch to produce either of the three cell types and the generation of the right number of them undergo complex genetic regulation. The components of these regulatory cascades vary between brain regions giving rise to the unique morphological and functional heterogeneity of this organ. Forkhead b1 (Foxb1) is a transcription factor gene expressed by NPCs in specific regions of the embryonic neuroepithelium. We used the mutant mouse line Foxb1-Cre to analyze the cell types derived from Fobx1-expressing NPCs (the Foxb1 cell lineage) from two restricted regions, the medulla oblongata (MO; hindbrain) and the thalamus (forebrain), of normal and Foxb1-deficient mice. Foxb1 cell lineage derivatives appear as clusters in restricted regions, including the MO (hindbrain) and the thalamus (forebrain). Foxb1-expressing NPCs produce mostly oligodendrocytes (OL), some neurons and few astrocytes. Foxb1-deficient NPCs generate mostly OPC and immature OL to the detriment of neurons, astrocytes and mature OL. The axonal G-ratio however is not changed. We reveal Foxb1 as a novel modulator of neuronal and OL generation in certain restricted CNS regions. Foxb1 biases NPCs towards neuronal generation and inhibits OPC proliferation while promoting their differentiation.
Highlights
Oligodendrocytes (OL) produce and maintain the myelin sheaths around axons of the central nervous system (CNS)
We use a Foxb1-Cre knockin-knockout mouse line together with reporter mouse lines Z/AP and ROSA26R in order to approach the following questions: (1) Which specific cell types of the CNS are generated by Foxb1-expressing ventricular zone (VZ)? (2) What is the role of Foxb1 in oligodendrocyte development? Our results show that Foxb1 is a novel player in OL development, whose role involves inhibiting Oligodendrocyte precursor cells (OPC) proliferation and promoting oligodendrocyte maturation
Foxb1 is expressed in two narrow longitudinal bands in the VZ of the brainstem (Alvarez-Bolado et al, 1999) reminiscent of the domains of expression of OPC marker genes Olig1 and oligodendrocyte transcription factor 2 (Olig2) (Zhou et al, 2000)
Summary
Oligodendrocytes (OL) produce and maintain the myelin sheaths around axons of the central nervous system (CNS). OL can provide trophic support to axons and promote their viability (Emery, 2010; Mitew et al, 2014). The process by which OL wrap axons in layers of myelin, cause severe pathological conditions in humans. Pathological conditions affecting the maturation of the brain white matter in premature infants are on the rise, and their most common result is mental retardation. Since myelination occurs mostly during CNS development, much research has focused on the development of OL. The mechanisms regulating the proliferation and differentiation of OL, the cells responsible for the formation of the white matter, are currently under intense scrutiny (Goldman and Kuypers, 2015; Marinelli et al, 2016)
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