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

48 NORMA L DEVELOPMENT
a smal l GTPas e tha t i s a Ra s famil y membe r
(Schwamborn and Puschel, 2004). The dat a indicate
that Ra p IB i s upstrea m o f bot h th e Pa r comple x
and Cdc4 2 wit h respec t t o axo n specificatio n
(Schwamborn an d Puschel , 2004) . I t is thought tha t
extracellular factors, a s yet unidentified, might medi -
ate th e effect s o f the loca l environmen t on polariza -
tion b y acting upstrea m fro m intracellula r signaling
molecules such as Rho, Par, and Rap IB.
Polarized Distribution of
Proteins an d Organelles
The difference s i n morphology and function that distinguish
axons and dendrites reflect different comple -
ments o f protein s an d organelle s i n eac h typ e o f
neurite. In the adult brain, certain proteins have a polarized
distribution , meanin g tha t the y ar e concen -
trated or even exclusively present in either dendrites or
axons. This asymmetr y must be created durin g development
b y compartment-specifi c traffickin g an d re -
tention o f thes e proteins . Th e Stag e 2 neurit e tha t
becomes the axo n in Stag e 3 typically receives more
organelles, cytosoli c proteins, and Golgi-derive d vesi -
cles than the processes that become dendrites (Bradke
and Dotti , 1997) . Intac t trafficking i s required for polarization,
as it is possible to prevent axon specification
by blockin g th e traffickin g o f Golgi-derive d vesicle s
with brefeldin A (Jareb and Banker, 1997). The polar -
ized distribution of some proteins may either promote
the emergin g difference s betwee n developin g axon s
and dendrites or simply reflect thos e differences . Th e
details o f how eac h polarize d protei n reache s it s appropriate
destination in one compartment bu t not the
other remain largely speculative.
The polarizatio n of proteins ma y resul t from re -
tention specifi c t o the appropriat e compartment. Experiments
with optical tweezers, which allow traction
force t o b e applie d t o specifi c proteins, sho w that a
barrier t o th e diffusio n o f some axon-specifi c mem -
brane protein s exist s a t th e axo n initia l segmen t
(Winckler et al, 1999; Fâche et al, 2004). The barrier
appears to be an accumulation of actin-tethered mem -
brane proteins . Analysis of phospholipid diffusio n i n
the membrane suggests that the diffusio n barrie r does
not exis t prio r t o axo n specificatio n (Nakad a e t al. ,
2003), but it may play an important role in subsequent
maturation. The exten t to which the diffusio n barrie r
is a cause or consequent of the establishmen t of neuronal
polarity remains unknown.
NEURITE MOTILITY
The neuroanatomis t Santiag o Ramon y Cajal (1894 )
observed tha t th e dista l exten t o f a growin g neurit e
"end[s] in a spherical conical swelling . .. with a large
number o f thick protrusions and lamella r processes, "
which he speculated wer e like "an amoebic mas s that
acts as a battering ram to spread the elements along its
path." H e name d thi s morphologica l specializatio n
the growth cone, and decade s of subsequent research
have supporte d hi s inferenc e that growt h cone s ar e
highly motile structures required for the elongation of
both axon s and dendrites . Much i s known about th e
structure and functio n of growth cones . The motilit y
of growth cone s depend s o n acti n an d microtubule s
and th e protein s tha t regulat e them . Additionally ,
growth cone s ar e th e sensor y organs for extracellular
cues that guide axons to engage in the directed growth
required for the establishmen t of correct connectivity.
Though muc h wor k remains t o be done , a n under -
standing o f ho w growt h cone s functio n i n neurit e
growth is emerging.
Growth Cone Structur e
Although neuronal growth cones vary considerably in
shape an d size , the y generall y share som e commo n
structural features. Most investigators recognize thre e
morphological zone s know n a s th e central , transi -
tional, an d periphera l domains, which are indicate d
in Figur e 4- 2 (Forsche r and Smith , 1988 ; Bridgman
and Dailey , 1989) . Th e relativel y thick centra l do -
main abut s th e neurit e an d i s enriched wit h micro -
tubules. The transitional domain, which lies between
the centra l an d periphera l domains , contain s mesh -
work, arcs , and radia l ridge s o f F-actin. Th e periph -
eral domai n consist s o f the lamellipodium , a wide,
flat region, and filopodia, which ar e fine membrane
protrusions tha t exten d distall y fro m th e lamel -
lipodium. The periphera l domain i s greatly enriched
with F-actin, organized a s meshwork and arc s in th e
lamellipodia. Filopodia contai n bundles of filaments
with th e barbe d ends pointing distally. Compared t o
the centra l domain , th e periphera l domai n ha s a
lower densit y o f microtubule s an d the y ar e notabl y
more dynami c (Schaefe r e t al, , 2002) . The leadin g
edge o f migrating fibroblasts was thought t o hav e a
structure similar to that of the neuronal growth cone.
Recent findings, however, show that the cytoskeletal
configuration an d mechanic s of motility in these two