Contribution of abnormal oligodendrocyte development to neurodevelopmental KBG syndrome

INTRODUCTION: KBG syndrome is a rare neurodevelopmental disorder (NDD) caused by mutations in the chromatin regulator gene ANKRD11 (ankyrin repeat domain 11). Chromatin regulators modify epigenetic signatures on many genes; therefore, mutations cause changes in global gene expression. KBG syndrome patients display aberrant brain development, global developmental delay, autism, and intellectual disability. The brain is built by neural stem cells, which must generate neurons and glia (non-neuronal cells oligodendrocytes and astrocytes) in a strict spatio-temporal manner. Our lab previously showed Ankrd11 regulates embryonic neural stem cell (NSC) proliferation and neurogenesis (formation of neurons). However, the role of Ankrd11 in glial cell formation is not known. This is an important question to address as oligodendrocytes (OL) are the only brain cells that form myelin (major white matter component), which is required for efficient neural communication. Aberrations in oligodendrocyte and myelin formation are linked to NDD pathology and symptoms. Oligodendrocytes can also be targeted pharmacologically to restore behaviour and cognition in NDD mouse models. Thus, the major objective of my project is to determine the role of Ankrd11 in oligodendrocyte and myelin development. METHODS: I used a novel mouse model where Ankrd11 is conditionally knocked out in NSCs using a Cre/Lox system (NestinCreERT2; Ankrd11fl/fl or Ankrd11nscKO). Ankrd11 knockout was induced with tamoxifen injection at embryonic day (E) 14, a time point prior to the start of oligodendrogenesis but after the formation of most neurons. Brain development was then analyzed during embryonic, postnatal, and adult time points. RESULTS: Oligodendrocytes develop from NSCs via a 2-step mechanism: 1) NSC to OPC (oligodendrocyte progenitor cell) commitment; and 2) OPC to OL differentiation. First, we corroborated that Ankrd11-deficient NSCs isolated from our novel KBG syndrome mouse model displayed reduced proliferation. I then showed that Ankrd11 knockout in embryonic NSCs does impact NSC commitment to OPCs but does lead to increased OPC proliferation in vitro and in vivo. By postnatal day P15, when OLs first develop, there was a significant increase in the density of mature OL in the white matter tracts (corpus callosum) of Ankrd11nscKO mice. This result was corroborated in vitro. Finally, Ankrd11nscKO mice displayed major brain structural changes during juvenile development, including enlarged lateral ventricle, which may be indicative of hydrocephaly. I am currently analyzing myelination in these mice using electron microscopy. CONCLUSIONS: We show Ankrd11 plays a key role in oligodendrocyte lineage cell formation. These results could help explain the mechanism of common phenotypes in patients and may provide novel paths for pharmacological intervention in children with KBG syndrome or other similar NDDs.