CELL BIOLOGY OF THE NEURON Polarity ... - Tavernarakis Lab

Cell Biology of the Neuron: Polarity, Plasticity and Regeneration, Crete 2011
Dendrite Morphogenesis and Functional Implications
Yuh-Nung Jan , HHMI, UCSF
For the past ten years, we have been trying to uncover the rules and the
mechanisms that control dendrite morphogenesis by using a group of fly larval
sensory neurons known as dendritic arborization (or da) neurons. We have gained
some insights about dendrite development including how axons are dendrites are
made differently, how a neuron acquires its neuronal type specific morphology,
how the dendrites of different neurons are organized, how the size of a dendritic
arbor is controlled, and how the pruning and remodeling of dendrites are
regulated during development. Of the four different classes of da neurons, the
dendrites of class IV da neurons form a regular array that tiles the larval body.
Recently we found those neurons actually constitute a novel photoreceptor system
using a photo-transduction pathway that is distinct from all the previously known
ones. This regular array of photo-sensors enable the larvae to sense light exposure
over its entire body to move out of danger.
Previously, we found that the Hippo pathway plays important roles in controlling
the dendritic arbor size and tiling of class IV da neurons. In Drosophila, Hippo
Kinase regulate Tricorner (Trc) and Warts (Wts), the the only two members of
Ser/Thr kinases of the NDR family in fly. Each Kinase then regulates
complementary aspects of dendritic arbors: Wts controls maintenance where as
Trc controls branching and tiling.
To see whether our findings could be extended to mice, we study the two Trc
homologues, NDR1 and NDR2, in mice. They share high sequence homology and
both are ubiquitously expressed in the mouse brain throughout development. We
find that NDR1/2 function to limit the complexity of the dendritic arbor of mouse
hippocampal and cortical neurons, a role analogous to that of their fly and worm
homologues. Additionally, we find a new function for NDR1/2: they are required
for the proper development of dendritic spines. In order to gain insights
concerning how NDR1/2 exert their functions, we set out to identify the
substrates of their kinase activity. In collaboration with our colleague Kevan
Shokat’s lab, we were able to apply their ingenious “chemical genetics and
covalent capture method” to identify five NDR1/2 substrates and their
phosphorylation sites. Strikingly, four have been implicated in vesicle trafficking.
We chose two of them, AAK1 and Rabin8, for further studies. We were able not
only to validate both as bona fide NDR1/2 kinase substrates but also found that
AAK1 is preferentially required for controlling dentritic arbor complexity
whereas Rabin8 is preferentially required for dendritic spine maturation – a
finding that paves the way for dissecting the NDR1/2 pathway.
Presented by: Jan, Yuh-Nung
63