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

newly postmitotic neuron s is particularly sensitive to
PCD throug h inhibitio n o f protein synthesis . Continuous
synthesis of anti-apoptotic proteins appears to be
important in the regulatio n o f PCD durin g neuronal
migration an d differentiatio n i n th e retin a (Rehen s
et al , 1999) . Consisten t wit h thi s hypothesis , mous e
embryos deficient for Bcl-xL, an anti-apoptoti c mem -
ber o f the Bcl- 2 family, exhibi t massiv e cell deat h of
immature neurons in the cerebra l corte x (Motoyama
et al, 1995). Bcl-xL is up-regulated i n early postmitotic
neurons a s they migrat e fro m th e V Z an d thi s hig h
level o f expression is maintained throug h adulthood .
On th e othe r hand, Bcl-x L expressio n is low in NPCs
(Motoyama et al, 1995).
In summary, ISEL+ results indicate that PCD i s
a commo n cel l fat e fo r NPC s throughou t th e
neural tube. Studie s involving inhibition of protein
FIGURE 5- 4 Identificatio n of newly postmitotic cell s
sensitive to apoptosis induced by inhibition of protein
synthesis. Immunolabeling for BrdU in the prolifera -
tive zone o f a retinal expiant (arrows ) after inhibitio n
of protein synthesis. Notice that the majorit y o f dying
cells (arrowheads) , identifie d a s globula r apoptoti c
bodies under differential interferenc e contrast, i s unlabeled
wit h BrdU . Scal e ba r = 20 \im. (Source:
Adapted from Rehe n e t al., 1999 )
CELL DEATH 7 9
synthesis i n th e developin g nervou s system and tar -
geted deletio n o f the anti-apoptoti c gen e Bcl-x L suggest
that during migration and initial differentiation,
the PC D machiner y i s controlle d b y suppresso r
proteins.
PROLIFERATIVE CELL DEATH, DNA
BREAKS AND END JOININ G
Thymic PCD occur s during the selection o f functionally
an d molecularl y distinc t thymocyte s (Sur h an d
Sprent, 1994), based on somatic DNA rearrangements
encoding T cell receptor s and immunoglobulins in T
and B lymphocytes, respectively. This process, known
as V(D)J recombination (Weaver and Alt, 1997) , i s responsible
for the unparallele d degree of immunologicai
diversit y tha t i s fundamenta l t o th e immun e
response. A s describe d above , a paralle l exist s be -
tween PCD i n the thymus and the feta l brain, where
cell death takes place in conjunction with cell prolif -
eration (Shortman et al, 1990 ; Chun, 2001).
ISEL+ result s suggest that a form o f cell selectio n
occurs i n th e neuroproliferativ e regions o f the brai n
and that the occurrence of PCD i s associated with the
maturation proces s (Blaschk e e t al. , 1996 , 1998) . I n
the feta l brain , the pea k of cell deat h coincide s wit h
the perio d whe n th e first neurons destine d t o com -
prise th e matur e corte x ar e bein g generate d (Cavi -
ness, 1982) . Thi s spik e i n PC D migh t allo w th e
selection o f the first cortical neuron s havin g desired
phenotypes which woul d serv e as a template fo r th e
selection o f later-generate d cells . Thi s hypothetica l
scenario leave s open th e questio n o f how cells migh t
be mechanistically selected .
Nearly a decade befor e geneti c recombinatio n was
formally demonstrated in lymphocytes, Dreyer and colleagues
(1967 ) postulate d tha t recombine d gene s en -
coding cell-surface proteins might play a part in guiding
the correct re-innervation of the goldfish tectum by retinal
axons . These recombine d protein s would act a s a
kind o f molecular cod e t o ensure that th e topographi -
cally correc t retinotecta l mappin g i s achieved. Sinc e
this idea was put forward, however, no gene undergoin g
the requisit e recombination i n the nervou s system has
been found . Thi s i s perhap s no t surprising , a s th e
reagents that were instrumental in the discovery of lymphocyte
V(D)J recombination—DNA sequences fro m
a known candidate locus, and clonal cell lines in which
the rearrangement even t takes place—do not currently
exist for the nervous system.