Healthcare and Medicine Reference
In-Depth Information
array of factors and receptors that keep motor neurons
alive during development (Oppenheim et al., 2001).
A second substance, glial cell line-derived neu-
rotrophic factor (GDNF), has been identified as pre-
venting naturally occurring motor neuron death in
vivo. GDNF was initially characterized by its ability
to keep midbrain dopaminergic cells alive in vitro.
This assay was chosen because Parkinson's disease
involves the death of these dopaminergic neurons, and
a survival factor may have important therapeutic
value (Lin et al., 1993). Four members of the GDNF
ligand family have now been isolated, and they all
belong to the TGF-b superfamily. Each ligand binds to
a specific ligand recognition a subunit (GFRa1
through 4). The GFRa subunits are attached to the
membrane by a glycosyl phosphatidylinositol anchor
(Figure 7.19). The ligand-receptor complex becomes
associated with a transmembrane tyrosine kinase,
called RET, and leads to its activation (Airaksinen and
Saarma, 2002).
There is now strong evidence that GDNF is an
endogenous, target-derived survival factor for a sub-
population of motor neurons. GDNF mRNA is found
in the limb, and GFRa and RET are expressed by
subsets of chick motor neurons during the period of
normal cell death (Homma et al., 2003). GDNF treat-
ment prevents naturally occurring motor neuron death
in chick embryos, and overexpression of GDNF in the
musculature of mice increased survival in most motor
neuron populations. Conversely, motor neuron death
was increased in GDNF-deficient mice (Oppenheim
et al., 1995; Oppenheim et al., 2000). The GDNF sig-
naling pathway influences more than just motor
neuron survival. Mice lacking either GDNF, Neurturin
(a second ligand), GFRa1, GFRa2, or RET also exhibit
specific loss of parasympathetic and enteric neurons
(Huang and Reichardt, 2001).
It is clear that motor neurons are a diverse popula-
tion, particularly in their dependence on trophic sub-
stances. Yet a third motor neuron trophic factors has
been reported, a cytokine called hepatocyte growth
factor/scatter factor (HGF/SF). As with GDNF,
HGF/SF influences the survival of only a subset of
motor neurons. In the chick, only lumber motor
neurons are dependent on HGF/SF for their survival
(Ebens et al, 1996; Yamamoto et al., 1997; Novak et al.,
2000).
Despite the expansion of candidate growth factors,
few of them seem to have an effect on the survival
of CNS neurons when they are eliminated from the
developing organism. One hypothesis is that central
neurons, unlike peripheral ganglion cells, have multi-
ple targets and afferents, perhaps giving them access
to many different growth factors during development.
The prediction from this hypothesis is that one must
eliminate two or more growth factors or receptors in
order to disrupt survival. It is also likely that many
survival factors have yet to be identified. For example,
the survival of embryonic retinal ganglion cells is
enhanced by tectal cell-conditioned media in a manner
that cannot be duplicated by CNTF or the neuro-
trophins (Meyer-Franke et al., 1995).
Afinal consideration is that many trophic factors
also promote certain aspects of differentiation (see
Chapters 2-4), and progress along these pathways may
be entangled with the decision to live or die. An inter-
esting example of this occurs in the developing fly eye.
The epidermal growth factor receptor (EGFR) medi-
ates a survival signal from a nearby cluster of postmi-
totic cells in the fly retina. In its absence, the number
of omatidial cells declines significantly. However, the
EGFR is also playing an important role in progression
through the cell cycle during this same period of time
(Baker and Yu, 2001).
ENDOCRINE CONTROL
OF CELL SURVIVAL
Hormonal signaling controls many aspects of devel-
opment, including cell survival. There are now several
examples of brain structures that are quantitatively
different in males and females of the same species,
often referred to as a sexual dimorphism. These sexual
dimorphisms are thought to arise from regional dif-
ferences in the amount of steroid hormones or their
receptors. Steroid hormones (e.g., estrogens and
androgens) are lipid soluble molecules that bind to
cytoplasmic receptors, and these receptors can translo-
cate to the nucleus where they regulate gene tran-
scription. For example, normal cell death among
developing superior cervical ganglion (SCG) neurons
is greater in female rats than in males. Furthermore,
castration of neonatal male rats significantly increases
the number of dying neurons, suggesting that a
gonadal hormone may be responsible for better
neuron survival in the male SCG. In fact, treatment
of neonatal animals with a sex hormone (estradiol or
testosterone) improves SCG neuron survival, even in
female animals (Wright and Smolen, 1987). Although
such discoveries have sparked much interest and the-
orizing about the neural substrates of male- and
female-specific behavior, there remain few solid exam-
ples that correlate structure to function. These are con-
sidered in more detail below (see Chapter 10).
The survival of some motor neurons is also depen-
dent on the presence of specific sex hormones. In the
Search Pocayo ::




Custom Search