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

qualitatively similar to, but les s severe, than tha t associated
with XRCC4 and Lig IV deficiency (Gu et al,
2000). Th e lac k o f a neurona l deat h phenotyp e i n
DNA-PKcs-deficient fetuses , alon g wit h th e milde r
phenotype o f K u deficienc y (vs . XRCC4 - o r Li g
IV-deficient fetuses) , is likely related t o relativ e low
fidelity of DNA end-joining in the backgroun d strain
of thes e mutants , show n b y a V(D)J recombinatio n
end-joining assay.
A intriguin g aspec t o f these studie s i s the consis -
tency of abnormal cell death pattern s i n the developing
cerebral cortex of mice deficien t in DN A ligase
IV, XRCC4 (Barne s et al, 1998 ; Fran k e t al, 1998 ;
Gao et al, 1998) , and Ku (Gu et al, 2000). Aberrant
death i s not observe d a t the earlies t embryonic ages,
and i t is not unti l th e perio d when mos t postmitotic
neurons ar e generated tha t dea d cell s ar e clearly observed
(Fig . 5-5) . Thi s genera l timin g i s seen i n al l
examined region s o f the neura l tube , includin g th e
spinal cord (Gao et al, 1998) .
These studie s provide the first evidence that evolutionarily
conserved gene s require d fo r completion o f
V(D)J recombination in lymphocytes are required for
normal neura l cel l surviva l i n th e developin g brain
(Gao e t al, 1998 ; Chun , 1999 ; Chu n an d Schatz ,
1999). Several NHEJ proteins have roles in NPC sur -
vival durin g the onse t o f neural differentiation . Th e
synthesis o f thes e protein s coul d b e crucia l fo r th e
normal behavior of newly postmitotic neurons during
their migration from proliferativ e zones to final destinations
in the CMS (Rehen e t al, 1996 , 1999) .
The absenc e of proteins important for the process
of immunologica l V(D) J recombinatio n promote s
cell death i n newly postmitotic neurons. This finding
suggests th e operatio n o f a nove l for m o f cell selec -
tion that distinguishes between neurons that make advantageous
DN A rearrangement s o r othe r genomi c
alterations and those that do not. What kin d of DNA
alterations could occu r i n NPCs within the develop -
ing brain?
ANEUPLOIDY, CELL SELECTION,
AND PROLIFERATIV E CELL DEATH
IN THE BRAI N
As discussed above, there i s indirect evidence fo r somatic
alteratio n o f th e genom e i n neuron s durin g
neurogenesis base d o n a growin g list o f molecule s
that functio n i n DN A recombination , repair , an d
CELL DEATH 8 1
surveillance (Ga o e t al , 1998 , 2000 ; Chun , 1999 ;
Chun an d Schatz , 1999 ; G u e t al , 2000 ; Le e e t al ,
2000; Rolig and McKinnon, 2000; Allen et al, 2001).
Many o f these molecule s ar e als o implicate d i n th e
genetic alteration s tha t ar e foun d i n cancers . On e
prominent geneti c abnormalit y i n cance r cell s i s
aneuloidy, a deviation from th e norma l diploid num -
ber of chromosomes. Th e associatio n between cance r
and neurodevelopmen t le d t o th e searc h fo r aneu -
ploidy a s on e expressio n o f genomi c chang e i n
neurons.
Direct assessmen t o f chromosome s i n dividin g
cells ca n b e performe d wit h spectra l karyotypin g
(SKY) which uses fluorescent labels to uniquely identify
eac h chromosome . Thi s technique reveal s that a
large fractio n o f NPC s harbo r chromosoma l abnor -
malities. Remarkably, one-third o f mouse NPCs have
gained o r los t at leas t on e o f their 4 0 chromosome s
(Fig 5-6 ; Rehe n e t al, 2001). NPCs isolated fro m th e
VZ o f the feta l mous e cerebra l corte x ar e ofte n ob -
served wit h on e o r mor e chromosome s displace d
from the mitotic spindle. Such chromosome displace -
ment suggest s tha t NPC s frequentl y mis-segregat e
their chromosomes , whic h ma y represen t on e wa y
that neurons can become aneuploi d during development
(Yan g et al, 2003).
Aneuploidy ha s als o bee n detecte d i n th e adul t
cerebral cortex , usin g interphas e fluorescen t i n sit u
hybridization (FISH ) t o visualize individual chromosomes.
In adult male cerebral cortex , FISH fo r X and
Y chromosomes show s that approximately 1 % of neurons
gained or lost a sex chromosome (Fi g 5-7) . Thi s
implies that a t least som e fractio n o f aneuploid cell s
that ar e produce d durin g neurogenesi s surviv e t o
adulthood. Theoretically , th e overal l percentag e o f
aneuploid neuron s i n th e adul t coul d b e muc h
higher than 1% , assuming the rat e of gain/loss is similar
fo r al l chromosome s (Kausha l e t al , 2003) , al -
though furthe r studie s ar e require d t o addres s thi s
issue.
Although some aneuploid cells survive, Aneuploid
cells may account for a significant proportion of PC D
during neurogenesis. Cell deat h i s likely a commo n
fate fo r aneuploid cells . I n cancers , man y cell s tha t
are thought to be dying have an altered genome. Further,
the high amount s of PCD in neuroproliferativ e
zones supports the ide a of a selection proces s against
undesirable geneti c abnormalities . A s a first approximation,
aneuploid y appear s t o b e generate d i n a
stochastic fashion . On e ca n speculat e tha t rando m