Protein kinase LKB1 regulates polarized dendrite formation of adult hippocampal newborn neurons

Adult-born granule cells in the dentate gyrus of the rodent hippocampus are important for memory formation and mood regulation, but the cellular mechanism underlying their polarized development, a process critical for their incorporation into functional circuits, remains unknown. We found that deletion of the serine-threonine protein kinase LKB1 or overexpression of dominant-negative LKB1 reduced the polarized initiation of the primary dendrite from the soma and disrupted its oriented growth toward the molecular layer. This abnormality correlated with the dispersion of Golgi apparatus that normally accumulated at the base and within the initial segment of the primary dendrite, and was mimicked by disrupting Golgi organization via altering the expression of Golgi structural proteins GM130 or GRASP65. Thus, besides its known function in axon formation in embryonic pyramidal neurons, LKB1 plays an additional role in regulating polarized dendrite morphogenesis in adult-born granule cells in the hippocampus.Granule cells are continuously being generated in the dentate gyrus of the adult hippocampus (1). These adult-born neurons play an important role in memory formation (2–4) and mood regulation (5, 6). Typically, developing granule cells assume a bipolar morphology, with highly branched dendrites extending toward the molecular layer, and a long thin axon projecting into the hilar area (7). This asymmetric structure provides the anatomical basis for directional information flow within the neuron, receiving input from the entorhinal cortex at the dendrite and sending axonal output to the CA3 region. However, little is known about the mechanism responsible for the polarization of these newborn neurons within the adult tissue environment, including the specification of a proper number of axons and dendrites, as well as the extension of these processes with proper orientation relative to the layer structure of the dentate gyrus.The serine/threonine protein kinase liver kinase B1 (LKB1) is a well-known regulator of cell polarity; it was originally identified as one of the six master regulators of anterior–posterior axis of the Caenorhabditis elegans zygote (8). Growing evidence indicates that LKB1 also plays important roles in cellular polarization in epithelial and other nonneural tissues in Drosophila and vertebrates (9–11). In the rodent central nervous system, LKB1 was shown to regulate axon formation and cell migration in embryonic cortical pyramidal neurons (12–14). However, it is unclear whether LKB1 also regulates other asymmetrical aspects of neuronal development, such as the polarized dendrite formation. Moreover, because LKB1 is also expressed in the adult brain, whether it plays a role in the morphogenesis of newborn neurons within the adult tissue environment remains to be determined.In this study, we used a retrovirus-mediated gene-transfer approach (15) to delete the LKB1 allele in adult-born hippocampal granule cells, and found that LKB1 is essential for polarized initiation of a single primary dendrite from the soma and oriented growth of its arbor toward the molecular layer. We also obtained evidence that the effect of LKB1 on polarized dendrite development is mediated by regulating the distribution of the Golgi apparatus in the cytoplasm. Together, the data from this study demonstrate a unique function of LKB1 in dendrite morphogenesis and suggest a cellular mechanism underlying its action.