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plantation or culture can reveal whether neuronal phe-
notypes are extrinsically regulated by the gene in ques-
tion, as in the case of a gene that codes for a secreted
factor, or intrinsically regulated, as in the case of a gene
that codes for the receptor to such a factor.
This chapter examines the several facets of cell fate
determination and differentiation, which have been
investigated using such techniques. Each aspect is
brought to light in a different system, and it is only
through looking at several systems that one can begin
to appreciate the full range of cellular and molecular
mechanisms that lead a set of relatively simple looking
progenitor cells to take on thousands of different
neuronal fates.
Intrinsically
determined
Progenitor
A
Progenitor
Progenitor
Leave in situ
Transplant
Transplant
Normal fate
Fate is uninfluenced
by host tissue
Fate is changed
by host tissue
B
C
Isolate in
culture
TRANSCRIPTIONAL HIERARCHIES IN
INVARIANT LINEAGES
Neighbor cell
Cell membrane
Signal molecules
Extracellular
As we discussed in Chapter 1, time-lapse studies of
the development of the nervous system of the nema-
tode C. elegans show that every neuron arises from an
almost invariant lineage (Figure 4.2). In this system,
the progenitors are uniquely identifiable by their posi-
tion and characteristic patterns of division. Ablation of
one of these progenitors usually leads to the loss of all
the neurons in the adult animal that arise from that
progenitor, indicating neighboring cells cannot fill in
the missing fates. This is called mosaic development.
To understand how these different precursors gener-
ate specific neurons, a genetic approach has been used,
and mutants have been found that interfere with the
development of particular neurons. These mutants are
then used to dissect the mechanisms of neuronal fate.
In this system, acquisition of neural identity is largely
the result of a multistep, lineage-dependent, process of
determination.
One of the best examples of such an analysis is that of
the specialized mechanosensory cells in nematodes
studied by Martin Chalfie and his colleagues (Chalfie
and Sulston, 1981; Chalfie and Au, 1989; Chalfie, 1993;
Ernstrom and Chalfie, 2002). Most nematodes wiggle
forward when touched lightly on the rear and backward
when touched on the front. By prodding mutagenized
nematodes with an eyelash hair attached to the end of a
stick, Chalfie and colleagues were able to find mutants
that had lost the ability to respond to touch. Many touch
insensitive worms have mutations in a group of genes
involved in the specification of the mechanosensory
cells. Mutations in the gene unc-86 result in the failure of
the mechanosensory neurons to form. Unc-86 encodes
a transcription factor that is expressed transiently in
many neural precursors and particularly in the lineage
Add signaling molecules
that influence cellular fate
Responding
cell
Transcription
factors
Gene expression
Cell attributes
FIGURE 4.1 A. Testing fate by transplantation. On the left, a
neural progenitor left in its normal environment turns into a partic-
ular type of neuron. In the middle, an intrinsically determined
progenitor's fate is unchanged by transplantation to a different envi-
ronment. On the right is an example of a progenitor whose fate is
determined extrinsically and so is changed by transplantation to a
different environment. B. An undifferentiated progenitor is placed
into a culture dish, and signaling molecules are tested, which may
influence the fate that the cell takes as it differentiates into a neuron.
C. An extracellular signal originating from one cell can influence the
fate of nearby cells by causing the responding cell to change its gene
expression pattern.
that influence determination, is genetic manipulations
such as mutational and transgenic analyses. Mutations
in particular genes can alter the fate of certain types of
neurons. With a genetic approach it is possible not only
to show where and when the normal fate decisions are
made but also to identify the gene product in question.
Forward genetics uses random mutagenesis to define
new genes that have effects on neural differentiation,
while reverse genetics uses molecular engineering to
knock out or overexpress particular genes (see Chapter
2) that are candidates for roles in neuronal fate determi-
nation or differentiation. Genetics combined with trans-
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