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

FIGURE 4- 2 Structur e o f the growt h cone . Th e mor -
phological zone s o f a growth con e ar e show n usin g a
differential interferenc e contras t micrograp h o f a dendritic
growth cone from a cultured ra t neocortical neu -
ron. Not e th e thic k centra l zon e (C) , separate d fro m
the fla t periphera l zon e (P ) b y th e transitiona l zon e
(T). Also , i n th e periphera l zone , th e lamellipodiu m
and several filopodia are indicated by dashed lines.
structures diffe r considerabl y (Strasse r e t al. , 2004) .
Thus, the presen t discussio n of growth con e motilit y
is confined to models from experiment s done o n neuronal
growth cones .
Growth Cone Motility
The exac t relationship between filopodial, lamellipodial,
an d neurit e motilit y i s no t completel y under -
stood. Filopodi a sampl e th e environmen t fo r cues to
determine th e directio n o f growth (O'Conno r e t al. ,
1990), and thus filopodial motility tends to reflect this
scanning patter n rathe r tha n demonstratin g a tigh t
link wit h neurit e growth . The movement s o f lamellipodia
are better correlate d with neurite growt h than
those o f filopodia , bu t lamellipodi a commonl y en -
gage i n extensio n an d retractio n tha t d o no t directl y
correlate with alterations i n the trajectory of the growing
neurite.
Growth con e motilit y requires dynamic regulation
of th e cytoskeleton . Th e treadmil l model , whic h i s
based on observations in filopodia, focuses on the rol e
of acti n (Fig . 4-3 ) (Li n e t al, 1994) . Filament s o f
actin are simultaneously polymerized at the dista l tips
of filopodi a an d retracte d proximall y b y myosi n
NEURONAL DIFFERENTIATION: FROM AXONS TO SYNAPSE S 4 9
FIGURE 4- 3 Th e acti n treadmil l mode l o f motility.
The tw o principle features of the treadmill model ar e
the retrograd e flo w o f actin, whic h i s due t o myosi n
motors, and the polymerization of actin at the leading
edge o f the filopodi a (o n right) . I f polymerization i s
faster tha t retrograd e flow , ther e i s forwar d move -
ment; i f it is slower, there i s retraction. Note that actin
is coupled t o the substrate by linker proteins that bind
transmembrane CAMs .
motors (Li n e t al., 1996) . I f the rat e of actin polymer -
ization a t the leadin g edg e i s greater than th e rat e of
actin retrograd e flow , th e filopodi a advances . I f polymerization
is slower than retrograde flow, the filopodia
retracts. If polymerization and retrograd e flow are balanced,
ther e i s no ne t chang e i n th e positio n o f th e
filopodia. The substrat e on which a neurite grows can
interact wit h transmembran e adhesio n molecules ,
which ar e attache d t o actin indirectl y via linker pro -
teins. Th e couplin g o f the substrat e t o th e acti n cy -
toskeleton (a ) allow s fo r th e generatio n o f tensio n
when force s are applied t o actin an d (b ) accounts for
the influenc e o f substrat e o n growt h con e motilit y
(Suter an d Forscher , 1998) . This mode l i s not com -
plete, a s axon s treate d wit h acti n depolymerizin g
agents stil l demonstrat e ne t growt h (Bentle y an d
Toroian-Raymond, 1986) , an d applicatio n o f rnicro -
tubule destabilizing reagents can prevent neurite out -
growth (Bamburg et al., 1986) . It should be noted that
current model s o f growt h con e motilit y ar e largel y
based o n experiments in unpolarized Aplysia neuron s
or in spinal or sensory neurons isolate d from frog s an d
chicks. Som e mechanism s o f growt h con e motilit y
may differ amon g species , cell types, and neurite type ,
but th e regulator y molecule s ar e likel y t o b e conserved.
A large an d divers e group o f proteins tha t modu -
late cytoskeleta l dynamic s throug h intracellula r
signaling o r direc t actio n i s involve d i n regulatin g
growth con e motility . Th e Rh o famil y o f proteins ,