Abstract: Judith STEGMÜLLER

Loss of the neuron-specific F-box protein FBXO41 results in developmental defects of the cerebellum and models an ataxia-like phenotype in mice

---

Judith StegmüllerAnna Holubowska, Chaitali Mukherjee, Nicola Schwedhelm-Domeyer

MPI of Experimental Medicine, Göttingen, Germany

---

The cerebellum is essential to motor coordination. Cerebellar development requires proper neuronal morphogenesis and migration to establish a functional network. In this study, we introduce the neuron-specific F-box protein FBXO41, which is exclusively expressed in the central nervous system (CNS). Mice lacking the FBXO41 gene exhibit a striking ataxic motor phenotype together with foliation defects and impaired migration of cerebellar granule neurons (CGNs) in the developing cerebellar cortex. We discovered that the centrosomal localization of FBXO41 and its interaction with disrupted in schizophrenia (DISC1) are important for FBXO41’s role in neuronal migration. In addition, we unraveled that FBXO41 forms a Cullin7 (Cul7)-based E3 ubiquitin ligase and that the integrity of the FBXO41-Cul7 complex is required to promote axon growth in CGNs. Finally, we identified the interaction of FBXO41 with axon growth-regulating Neurofilament M (NFM), whose ubiquitination by FBXO41-Cul7 results in stabilization. Collectively, we established FBXO41 as a key regulator of cerebellar development.