Authors Josh Sanes (left) and Brendan Lilley
Directional flow of information within the nervous system depends upon the ability of neurons to divide themselves into discrete compartments. Most neurons have a single axon that transmits information and multiple dendrites that receive information. The axons of one neuron are connected to the dendrites of others via synaptic connections, which process and relay information to the neuronal soma and then to the axon for transmission to dendrites and so on. Proper polarization of neurons during development is therefore essential for circuit function. In the May 4th issue of Cell, MCB researchers Brendan Lilley, Albert Pan and Joshua Sanes report on a molecular cascade that is responsible for establishing the polarity of cortical neurons in the developing brain. Their results are reported in an article coauthored by Franck Polleux and colleagues at UNC Chapel Hill, and are accompanied by an independent, complementary report from Mu-Ming Poo and colleagues at UC Berkeley.
The Sanes lab became interested in neuronal polarization while studying the SAD-A and SAD-B kinases, which were found to be essential for neuronal polarization in vivo. In an effort to understand the regulation of SAD kinases, they looked to LKB1, a kinase mutated in the cancer predisposition disorder, Peutz-Jehgers syndrome. LKB1 regulates epithelial cell polarity in mammals while its orthologs in worm and fly are essential for establishing polarity of the embryo. Furthermore, LKB1 was known to activate multiple kinases of a subfamily of which SAD-A and -B are members. The Sanes and Polleux labs teamed up to characterize the role of LKB1 in neuronal polarity and to investigate a possible connection to SAD kinases. Using a conditional gene inactivation approach that restricted LKB1 loss of function to the developing cortex, they demonstrated that LKB1 is required for the formation of axon tracts that connect the cortex to other structures in the central nervous system. Conversely, when extra LKB1 was supplied to neurons, they grew multiple axons.
Further studies showed that LKB1 is central to a pathway that leads to appropriate polarization of brain neurons. Poo and colleagues provide evidence that the choice of which process becomes an axon is influenced by factors secreted from neighboring cells. Some of these factors, including one called BDNF, activate yet another kinase called TrkB. TrkB in turn leads to activation of a kinase called PKA, which then activates LKB1. LKB1 then phosphorylates and activates SAD kinases, which were already implicated in polarization in previous work from the Sanes lab. Finally, SAD kinases phosphorylate proteins that give axons and dendrites their distinct characters.
Together, these studies establish LKB1 and SAD kinases as central players in a pathway of at least 5 kinases. This multi-kinase signaling pathway regulates the polarization of cortical neurons in vivo, among the earliest steps in the formation of neural circuits. The complexity of this kinase cascade may provide a way for neurons to integrate multiple signals, thereby achieving fine control over a critical aspect of brain development. Does this same pathway regulate polarity in all neurons or just those of the cortex? That is what Lilley and Sanes are asking now.