Tbx1 Heterozygosity in the Oligodendrocyte Lineage Shifts Myelinated Axon Composition in the Mouse Fimbria Without...

Constitutive heterozygosity of Tbx1, a T-box transcription factor gene in the 22q11.2 deleted region, produces behavioral deficits and alters myelinated axon composition in the mouse fimbria. However, the cellular origins of these effects-and whether axon changes causally drive behavioral impairments-remain unclear. Prior data link Tbx1 heterozygosity to reduced oligodendrocyte precursor cell (OPC) markers in the fimbria in mice, raising the hypothesis that Tbx1 deficiency specifically in the oligodendrocyte lineage contributes to myelin and behavioral phenotypes. To test this hypothesis, we first showed via in vitro siRNA knockdown that Tbx1 regulates both OPCs and mature oligodendrocytes. We then generated conditional PdgfrαCre;Tbx1+/flox mice to initiate Tbx1 heterozygosity in OPCs. These mice exhibited Cre-mediated recombination in Pdgfrα-expressing brain regions and OPC progeny in the fimbria. At 1 month of age, male mutants displayed enhanced spontaneous alternation in the T-maze relative to wild-type littermates-an effect absent at 2 months. No differences appeared in neonatal ultrasonic vocalizations, social interaction, novel object approach, anxiety-like behavior (elevated plus maze), or open-field locomotion and thigmotaxis. Electron microscopic analysis demonstrated a compositional shift in myelinated axons within the fimbria of adult male mutants: increased numbers in the 300-800 nm diameter range and decreased numbers at ~ 1,200 nm and ~ 1,400 nm, with unchanged myelin thickness across diameters. These results demonstrate that Tbx1 heterozygosity in the oligodendrocyte lineage drives a selective shift toward smaller myelinated axons in the fimbria and a transient cognitive enhancement but does not recapitulate the full myelination abnormalities or the broader cognitive/social deficits observed in constitutive Tbx1 heterozygotes. Thus, Tbx1 function in non-oligodendrocyte lineage cells likely exerts non-cell-autonomous effects on myelination that contribute to neurodevelopmental behavioral impairments.