Opposing Roles forHoxa2andHoxb2in Hindbrain Oligodendrocyte Patterning

Abstract

Oligodendrocytes are the myelin-forming cells of the vertebrate CNS. Little is known about the molecular control of region-specific oligodendrocyte development. Here, we show that oligodendrogenesis in the mouse rostral hindbrain, which is organized in a metameric series of rhombomere-derived (rd) territories, follows a rhombomere-specific pattern, with extensive production of oligodendrocytes in the pontine territory (r4d) and delayed and reduced oligodendrocyte production in the prepontine region (r2d, r3d). We demonstrate that segmental organization of oligodendrocytes is controlled byHoxgenes, namelyHoxa2andHoxb2. Specifically,Hoxa2loss of function induced a dorsoventral enlargement of theOlig2/Nkx2.2-expressing oligodendrocyte progenitor domain, whereas conditionalHoxa2overexpression in theOlig2⁺domain inhibited oligodendrogenesis throughout the brain. In contrast,Hoxb2deletion resulted in a reduction of the pontine oligodendrogenic domain. CompoundHoxa2^−/−/Hoxb2^−/−mutant mice displayed the phenotype ofHoxb2^−/−mutants in territories coexpressingHoxa2andHoxb2(rd3, rd4), indicating thatHoxb2antagonizesHoxa2during rostral hindbrain oligodendrogenesis. This study provides the firstin vivoevidence thatHoxgenes determine oligodendrocyte regional identity in the mammalian brain.