Brain Development: Normal Processes and the Effects of Alcohol ...

50 NORMA L DEVELOPMENT
which ca n influence both th e actin an d microtubule
cytoskeleton, play s a n importan t rol e i n regulatin g
growth con e motility . Th e contro l o f actin polymer -
ization at the leadin g edge o f growth cones i s an area
of activ e study . Member s o f th e Ena/Vas p family ,
which prevent barbed acti n capping , ca n regulate th e
behavior o f filopodi a (Lebran d e t al. , 2004) . Othe r
molecules tha t ma y pla y role s i n acti n dynamic s at
the leadin g edg e includ e profilin , fascili , an d acti n
depolymerizing factor/cofili n (Will s e t al. , 1999 ;
Meberg an d Hamburg , 2000 ; Coha n e t al, 2001) .
Further wor k i s require d t o construc t a cohesiv e
model o f how thes e an d othe r protein s regulat e cy -
toskeletal dynamics at the leading edge o f the growth
cone.
Directed Growth
Growth cone s ar e generall y considered t o mediat e
the respons e o f growing axons and dendrite s t o th e
myriad of guidance cue s that direct the establishmen t
of appropriate connectivity. It i s possible t o alter th e
trajectory o f neurite growth by applying a gradient of
a chemotropi c molecul e t o a growt h con e i n vitr o
(Zheng e t al. , 1994) . I n fact , thi s assa y i s now com -
monly use d t o tes t whether a protei n ca n serv e a s a
guidance cue. Furthermore, many receptors for known
guidance cues are expressed in the plasma membrane
of growth cones. I t is believed that gradients of guidance
cue s acros s the surfac e o f the growt h con e pro -
duce asymmetri c effect s o n receptor s tha t mediat e
growth cone steering (Goodman, 1996) .
The respons e o f growt h cone s t o guidanc e cue s
depends o n bot h th e acti n an d microtubul e compo -
nents o f the cytoskeleto n and th e effector s tha t regu -
late them downstrea m from guidance receptors . I t has
been propose d that growth cone turning occurs when
actin i s polymerize d asymmetricall y withi n th e
growth cone and when there i s a subsequent increase
in microtubul e entry into and polymerizatio n in th e
actin ric h zone (Den t and Gertler, 2003) . Consistent
with this model, disruptions of regulators of either the
actin o r th e microtubul e cytoskeleto n ca n resul t i n
defective axo n guidance. Example s include the actin
interactors Arp2/3 and Ena/Vas p (Lanier et al., 1999 ;
Lee e t al, 2004 ; Strasse r e t al, 2004 ) a s well a s the
microtubule interactors , plu s end-trackin g protein s
(Lanier et al, 1999 ; Lee et al, 2004). The precise significance
of these molecules in directed growth, however,
remains a subject of active investigation.
Several molecule s tha t ca n signa l betwee n guid -
ance receptor s an d th e cytoskeleto n i n growt h cone s
have been identified. Rho family members, which can
regulate both acti n and microtubules, have been im -
plicated i n signalin g downstrea m fro m guidanc e
receptors (Gua n an d Rao , 2003) . Also, relativ e con -
centrations o f cycli c nucleotide s (cycli c adenosin e
monophosphate [cAMP ] an d cycli c guanosin e
monophosphate [cGMP] ) can modulate the respons e
of growth cones to guidance cues . For instance, a gradient
of brain-derived neurotrophi c facto r (BDNF), a
factor tha t i s usuall y attractive fo r Xenopus growt h
cones, becomes repulsive if the growth cone is treated
with a cAM P inhibito r (Song e t al, 1997) . Anothe r
potential signal downstream from guidanc e receptor s
is Ca 2+ . Liv e imagin g o f growt h cone s i n cultur e
shows that transient increases in Ca 2+ o n one sid e of
the growt h con e correlat e wit h turnin g towar d th e
contralateral side (Gomez e t al., 2001). Interestingly,
larger Ca z+ transients can result in ipsilateral turning.
This paradox i s explained b y data indicatin g that low
concentrations o f Ca 2+ ac t primaril y throug h cal -
cineurin phosphatase, whereas higher concentration s
act vi a calcium-calmodulin-dependen t protei n ki -
nase I I (We n e t al. , 2004) . The recen t findin g tha t
Ca 2+ concentrations i n the growth cone can be mod -
ulated by cAMP and cGMP control of calcium chan -
nels suggests that Ca 2+ acts on growth cone guidanc e
downstream fro m th e cycli c nucleotides (Nishiyama
et al., 2003). Though data on interactions between receptors,
signals , effectors , an d th e cytoskeleto n ar e
emerging, muc h remain s to b e don e befor e a com -
plete model o f how a specific guidance cu e result s in
a change i n growth cone motilit y can be constructed .
AXON GUIDANCE
In th e lat e nineteent h century , Ramon y Cajal pro -
posed tha t axon s coul d b e guide d chemotropically ,
but the ide a fel l ou t of fashion and was untested until
it was revisited by Roger Sperry in th e 1940 s (Sperry,
1963). I n a serie s of classic experiments, Sperr y severed
a frog optic nerve, rotated the eye 180°, and then
allowed connections t o form again. These frogs mad e
180° error s i n their attempt s t o catch flies. In contra -
diction to the popular view, including that of his thesis
advisor , Sperr y conclude d tha t th e regenerate d
axons di d no t innervat e ne w targe t region s t o com -
pensate fo r th e ey e rotation , bu t projecte d t o thei r