Olfactory bulb anomalies in KBG syndrome mouse model and patients

Abstract

ANKRD11 (ankyrin repeat domain 11) is a chromatin regulator and the only gene associated with KBG syndrome, a rare neurodevelopmental disorder. We have previously shown that Ankrd11 regulates murine embryonic cortical neurogenesis. Here, we show a novel olfactory bulb phenotype in a KBG syndrome mouse model and two diagnosed patients. Conditional knockout of Ankrd11 in murine embryonic neural stem cells leads to aberrant postnatal olfactory bulb development and reduced size due to reduction of the olfactory bulb granule cell layer. We further show that the rostral migratory stream has incomplete migration of neuroblasts, reduced cell proliferation as well as aberrant differentiation of neurons. This leads to reduced neuroblasts and neurons in the olfactory bulb granule cell layer. In vitro, Ankrd11-deficient neural stem cells from the postnatal subventricular zone display reduced migration, proliferation, and neurogenesis. Finally, we describe two clinically and molecularly confirmed KBG syndrome patients with anosmia and olfactory bulb and groove hypo-dysgenesis/agenesis. Our report provides evidence that Ankrd11 is a novel regulator of olfactory bulb development and neuroblast migration. Moreover, our study highlights a novel clinical sign of KBG syndrome linked to ANKRD11 perturbations in mice and humans.

The chromatin regulator Ankrd11 controls cardiac neural crest cell-mediated outflow tract remodeling and heart function

“…We and others have also shown that Yoda mice or mice with Ankrd11 knockdown in cortical progenitors and their derivatives have impaired neurogenesis and neuron positioning, which may suggest altered neuronal migration 13 , 76 . This was recently corroborated in our study, which showed that Ankrd11 knockout in neural stem cells leads to severe neuroblast migration defect in the rostral migratory stream 75 . Together, the results presented in this study and previous reports suggest that Ankrd11 may have unique roles in each cell type it is expressed in and that Ankrd11’s function may depend on cellular identity and environment.…”

“…However, we also showed a decrease in cell proliferation in some, but not all, craniofacial regions, with no difference in apoptosis 28 . Moreover, our work with Yoda mice, which carry a heterozygous splice site-like mutation in Ankrd11 , or with mice that have Ankrd11 knocked down or out in neural stem cells, shows that Ankrd11 regulates embryonic neural stem cell proliferation 13 , 75 . We and others have also shown that Yoda mice or mice with Ankrd11 knockdown in cortical progenitors and their derivatives have impaired neurogenesis and neuron positioning, which may suggest altered neuronal migration 13 , 76 .…”