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

of disease or injury, dyin g cell neighbor s ma y exhibit
different mode s o f cell deat h an d a n individua l cel l
may exhibit features of different modes .
One importan t poin t t o conside r i n cel l deat h i s
that the lif e o f a critically damaged cel l ma y be tem -
porarily maintained, but i t will likely die. That is, the
blocking of one mode of cell death ma y merely cause
a cell to shift to another mode of cell death. Thus, the
outcome i s that the cel l still dies, but i t may do so by a
different sequenc e o f event s (e.g. , D'Mell o e t al, ,
2000; Denecker et al, 2001; Zhou et al., 2005). Alternatively,
blocking of cell death may allow cell survival,
which is not necessarily a good thing. Fo r example, in
mice deficien t i n apoptosi s protease-activatin g facto r
(APAF) 1 , caspase 3 , o r caspas e 9 , ther e i s a lac k o f
cell deat h i n the neura l tube , and thi s prevent s normal
closur e o f th e tub e (Kuid a e t al. , 1996 , 1998 ;
Cecconi e t al, 1998 ; Hake m e t al, 1998 ; Yoshid a
et al, 1998 ; Honarpou r et al, 2000). It should als o be
considered that enhanced cel l deat h i s not th e etiol -
ogy of a pathological state, rather, neuronal death is a
process or end poin t associated with a given disease.
Apoptosis
The ter m apoptosis wa s coined t o describe a series of
morphological step s throug h whic h dyin g cells pass
(Kerr e t al. , 1972) . With furthe r study , apoptosis has
become associate d with a metabolically active process
(e.g., Wyllie, 1997 ; Putch a an d Johnson , 2004) . Accordingly,
chromosoma l DN A i s cleaved , th e chro -
matin condenses , an d th e nucleu s i s broke n int o
small pieces . Eventuall y the cel l shrink s and breaks
into small , membrane-boun d apoptoti c bodie s tha t
are engulfe d b y neighborin g cell s o r macrophages .
This mechanism ensures that proteolytic enzymes are
contained withi n membrane-boun d entitie s and tha t
the apoptoti c cel l die s withou t causin g deat h o f
neighboring cells.
Much o f the initia l fundamental information on
the pathway s of apoptosi s cam e fro m studie s o f th e
nematode C. elegans (e.g., Horvitz et al., 1983 ; Hent -
gartner an d Horvitz , 1994 ; Reddie n an d Horvitz ,
2004). O f the 109 0 cell s produced durin g the devel -
opment of C. elegans, 13 1 die. Products o f two genes
are essentia l for this death: Ced 3 and Ced 4 (Horvitz
et al., 1983 ; Ellis and Horvitz , 1986). Los s or inactivation
o f eithe r o f these gene s prevent s cel l death . I n
the 95 9 cells that do not die , the produc t o f another
gene, Ced9 , bind s t o Ced4 , an d prevent s i t fro m
INTRACELLULAR PATHWAY S OF NEURONAL DEATH 9 3
activating Ced3. Mammalian homolog s of these critical
genes hav e been identified. Ced3 is homologou s
with th e caspas e family , Ced 4 wit h APAF-1 , an d
Ced9 wit h th e Be l family . Althoug h th e gene s an d
gene product s involve d i n apoptosi s are highl y con -
served acros s species , th e mammalia n pathway s are
considerably mor e comple x an d convolute d tha n
those identifie d in C . elegans. For example, differen t
pathways of apoptosis ar e invoke d in cerebellar granule
cell s dependin g o n whethe r th e cell s ar e pre- or
postmigratory (Lossi et al., 2004).
As state d above , us e o f th e ter m apoptosis ha s
changed ove r the years . The definitio n ha s been re -
worked fro m a se t o f morphologica l feature s t o in -
clude molecula r an d biochemica l features . Putch a
and Johnson (2004) suggest that apoptosis b e reserved
for a caspase-dependen t cel l deat h tha t cause s th e
morphological features described by Kerr et al. (1972;
see above) . They conten d tha t caspase-independen t
cell deat h i s nonapoptotic , despit e acknowledgin g
that i t would b e possibl e t o see apoptotic morpholg y
without caspas e activation . Man y researcher s us e
apoptosis an d programmed cell death interchange -
ably, bu t thi s i s inappropriat e becaus e a program
connotes geneti c determination , a s i n th e cas e o f
C. elegans. In mammalian systems , this type of genetic
deat h i s rare , an d mos t apoptoti c deat h result s
from environmenta l factors . I n thi s case , apoptoti c
death i s best considere d a s naturall y occurring cel l
death. I n this chapter, apoptosis include s morpholgi -
cal and biochemical events .
Major Component s of
Apoptotic Pathways
Bel Family
Bel protein s play pivotal roles i n cel l death . I n contrast
to C. elegans, which only expresses a single gene,
Ced9, many organisms have multiple member s of this
family. Ther e ar e tw o functionall y distinc t group s
within th e Be l family : thos e tha t induc e deat h an d
those that protect against death. Bel proteins can also
be subdivide d structurally: there ar e three subgroup s
defined b y th e numbe r o r typ e o f Bcl- 2 homolog y
(BH) domains. Anti-apoptotic members o f the family ,
including Bcl-2 , Bcl-x L, Bcl-w , Mcl-1 , an d Al/Bfl-1 ,
contain fou r B H motifs : BH1 , BH2, BH3 , an d BH4 .
Pro-apoptotic member s ma y b e i n on e o f tw o sub -
groups: (1 ) those tha t contai n multipl e B H domain s