Biomedical Engineering Reference
In-Depth Information
5. CELSR2 AND CELSR3 IN BRAIN WIRING
Functional neuronal networks are crucial for brain function. Network
formation is finely orchestrated at the cellular and molecular levels by genetic
programs and interactions with the environment. After reaching their loca-
tion, postmitotic neurons extend axons that are guided to their targets by
intrinsic programs, guidepost cells, and attractive and repulsive molecular
cues. They ramify receptive dendritic fields according to tiling rules. In ad-
dition to their role in neuronal migration,
Celsrs
are implicated in dendrite
development and axon guidance, from
Caenorhabditis elegans
and Drosophila
to mammals (
Berger-Muller & Suzuki, 2011; Gao, Kohwi, Brenman, Jan, &
Jan, 2000; Matsubara, Horiuchi, Shimono, Usui, & Uemura, 2011
).
In flies, sensory neurons extend dendrites dorsally toward the midline.
Dendrites fromhomologous neurons in the two opposite hemisegments avoid
each other, leading to a dendrite-free zone near the dorsal midline. This re-
ciprocal inhibition of dendrite growth, akin to tiling, is defective in fmi/stan
mutants, where dendrites do grow across the midline to occupy fields over-
lapping those of homologous neurons (
Gao et al., 2000
). A role for fmi/stan in
the tiling of dendrites is further supported by the identification of fmi/stan
mutants in genetic screens for aberrant dendritic extension of mushroom
body neurons (
Reuter et al., 2003
). The function of fmi/stan in dendrite
growth does not rely solely on adhesion mediated by the extracellular domain
because overexpression of an N-terminally truncated fmi that lacks cadherin,
EGF-like, and laminin G motifs rescues the dendritic phenotype partially
(
Kimura, Usui, Tsubouchi, & Uemura, 2006
). Intriguingly, neither loss or
gain of function of
frizzled
nor overexpression of
dsh
phenocopy the
fmi/stan
dendritic phenotype. Moreover, to our knowledge, no such phenotype has
been described in other PCP mutants. In the mammalian nervous system,
Celsr2
is required for the maintenance of dendritic arbors: RNAi-induced
downregulation of
Celsr2
in brain slices reduces the length of dendrites in cor-
tical pyramidal neurons, and the complexity of dendritic trees of Purkinje cells
(
Shima, Kengaku, Hirano, Takeichi, & Uemura, 2004
). By contrast, the si-
lencing of
Celsr3
results in dendrite overextension. The opposite effects of
Celsr2 and Celsr3 are related to a single amino acid change in the first intra-
cellular loop: like fmi/stan, mammalian Celsr3 has a histidine at position 2413,
and both repress growth and/or induce retraction of dendrites. That histidine
residue is replaced with an arginine in Celsr2, which promotes dendrite
growth and maintenance (
Shima et al., 2007
).
