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initially unresponsive to nerve growth factor (NGF)
because they do not express the NGF receptor. One of
the effects of FGF is to induce the NGF receptor gene,
thereby making the SA cells responsive to NGF, which
stimulates their differentiation and survival as neurons
(Anderson, 1993).
Sympatho-adrenal (SA) progenitors can also be iso-
lated from the adrenal gland primordium of embry-
onic mammals and raised in culture; they give rise to
two very different types of cells, the adrenergic sym-
pathetic neurons and the endocrine chromaffin cells.
Prior to differentiation, all SA progenitors express
markers for both cell types. When SA progenitors are
exposed to glucocorticoid hormone in vitro , which
normally is produced in the adrenal gland, they
develop as chromaffin cells. Glucocorticoids are
steroid hormones that act on cytoplasmic receptors.
After binding to the hormone (ligand) the receptor-
ligand complex is transported to the nucleus where it
acts as a transcription factor, binding to DNA and acti-
vating or repressing certain genes. In the case of the
SA progenitor, glucocorticoids suppress the transcrip-
tion of neuron-specific genes and activate the tran-
scription of chromaffin cell-specific genes.
All sympathetic neurons start life producing the neu-
rotransmitter noradrenalin. They receive the signal to
be adrenergic. The Phox2b and MASH1 transcription
factors induced by BMPs secreted by the aorta (Reiss-
mann et al., 1996; Pattyn et al., 1999) (Figure 4.15)
appear to be responsible for controlling the expression
of tyrosine hydroxylase, a key member of the synthetic
pathway for this transmitter. Many of these neurons
send out axons to smooth muscle targets; these sym-
pathetic neurons remain adrenergic throughout life.
However, a few sympathetic neurons, for example,
those that innervate sweat glands, switch their neuro-
transmitter phenotype late in development and become
cholinergic; that is, they secrete the neurotransmitter
acetylcholine (ACh). Neurotransmitter choice in these
cells is a late aspect of cell fate that is regulated by the
target (Francis and Landis, 1999). The fibers innervating
sweat glands begin to turn off tyrosine hydroxylase and
other adrenergic enzymes and begin to make choline
acetyltransferase, the synthetic enzyme for ACh pro-
duction (Figure 4.16). Evidence for the role of the sweat
glands themselves in inducing the switch in pheno-
types comes from transplantation experiments. Trans-
planting foot pad tissue, rich in sweat glands, to areas of
the body that usually receive adrenergic sympathetic
innervation leads to the induction of cholinergic
function in the sympathetic axons that innervate the
transplanted glands. Factors such as interleukin-6
are capable of causing an adrenergic-to-cholinergic
switch in phenotype and have been purified from
Dorsal aorta
(BMP-2, BM P-4,
and BMP-7)
Aorta + neural crest
BMP-7 + neural crest
Adregenic neurons
FIGURE 4.15 Control of transmitter phenotype by the aorta.
A. Neural crest cells that migrate close to the aorta often become
sympathetic ganglia with adrenergic neurons. The dorsal aorta is a
source of BMPs. B. When neural crest cells are cultured with aorta
or BMP-7, they turn on Phox2b, which activates the transcription of
tyrosine hydroxylase and the cells become adrenergic neurons.
culture media, but the actual factor that operates in
sweat glands to produce this effect in vivo has not yet
been definitively identified. Nevertheless, these experi-
ments make it clear that targets can retrogradely deter-
mine that transmitter type of the innervating neurons.
In the vertebrate peripheral nervous system, all glia,
whether they are Schwann cells or glial support cells in
the sensory and autonomic ganglia, arise from the
neural crest and express Sox10 . But the decision to
express Sox10 and commit to a glial fate happens late in
the crest decision hierarchy, after the decision to be
sensory or autonomic. A secreted protein called
Neuregulin-1 (Nrg-1) induces crest cells to adopt glial
fates (Britsch et al., 2001; Leimeroth et al., 2002) (Figure
4.17). When migrating crest cells are cultured in the
absence of added Nrg-1, the majority of clones contain
both neurons and glial cells, but if Nrg-1 is applied,
most clones develop as pure glia. Neural crest cells
express Nrg-1 only after they have migrated peripher-
ally and coalesced into distinct masses as in the dorsal
root or sympathetic ganglia. In fact, Nrg-1 is expressed
only in those cells that have already started to exhibit a
neuronal phenotype. The Nrg-1 receptor is expressed
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