Role of Transcription Factor Foxb1 in Oligodendrocyte Development

Abstract

Oligodendrocytes are the myelin-forming cells of the white matter of the central nervous system (CNS). Oligodendrocytes are derived from Oligodendrocyte Progenitor Cells (OPC) or from Neural Stem Cells (NSC) at different development stages. Although numerous factors involved in oligodendrocyte production have been identified, the transcriptional control of oligodendrocytogenesis remains largely unknown. However, the treatment of demyelination diseases like multiple sclerosis (MS) and periventricular leukomalacia (PVL) could greatly benefit from this knowledge. The forkhead (Fox) gene family encodes transcription factors characterized by a DNA binding domain with a variant of the helix-turn-helix configuration. Foxb1 encodes a forkhead transcription factor expressed in the mouse neural plate and early mesoderm in the primitive streak stage. In midgestation, Foxb1 is expressed in restricted areas of the neuroepithelium (ventricular zone) as well as the brain parenchyma of midbrain, thalamus, hypothalamus, superior and inferior colliculi, pons, medulla oblongata and spinal cord. Preliminary work in our lab showed that the number of CNS cells belonging to the Foxb1 lineage (i.e. born from Foxb1-expressing ventricular zone) is much larger than the number of CNS cells actually express Foxb1 in the adult mouse. For my PhD work I wanted to know, first, which CNS cells are generated by Foxb1-expressing NSC; second, I wanted to learn about the specific function of Foxb1 in those cells. To approach those questions I analyzed the phenotype of heterozygous (Foxb1Cre/+) and homozygous (Foxb1Cre/Cre) mice of the knock in-knock out Foxb1-Cre-EGFP mouse line (generated previously in our lab). I found that the Foxb1-expressing neuroepithelium generates large numbers of oligodendrocytes (as well as some astrocytes and neurons); in mice deficient in Foxb1, immature oligodendrocytes as well as OPC are abnormally abundant but can differentiate into oligodendrocytes able to produce normal myelin sheaths. I concluded that transcription factor Foxb1 is a novel player in the regulation of OPC generation, on which it exerts a potent inhibitory function.