The Golgi-associated microtubule cross-linking protein MTCL2 promotes the multipolar extension of dendrites in cerebellar granule neurons

The dynamic regulation of neuronal polarity is essential for establishing neural networks during brain development. The primary culture of rodent neurons recapitulates several aspects of this polarity regulation and thus provides powerful tools for revealing the cellular and molecular mechanisms underlying axon specification and neuronal migration. However, little is known about how preexisting bipolarity breaks to form multipolar dendrites. Here, we demonstrated that the Golgi-associated, microtubule (MT) cross-linking protein MTCL2 plays an essential role in this type of polarity change observed in the differentiation of cerebellar granule neurons (CGNs). MTCL2 is highly expressed in CGNs and exhibited gradual accumulation in dendrites in parallel to their polarity development. MTCL2 depletion resulted in the generation of longer and fewer dendrites by suppressing the bipolar-to-multipolar transition of dendrite extension observed in the normal polarization process. During this process, the Golgi apparatus changes its localization from the base of the preexisting bipolar neurites to the lateral or apical side of the nucleus, where it associates closely with the MT cage wrapping the nucleus. The resulting upward extension of the Golgi apparatus is tightly coupled with randomization of its position in x-y plane. Knockdown/rescue experiments demonstrated that MTCL2 promotes these changes in Golgi position in an MT- and Golgi-binding activity-dependent manner. These results suggest that MTCL2 promotes the development of multipolar short dendrites by sequestering the Golgi apparatus from the base of preexisting neurites, enabling its random movements around nuclei.