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Volume 17, Number 10,
Issue of May 15, 1997
pp. 3644-3652
Copyright ©1997 Society for Neuroscience
Mash1 and neurogenin1 Expression Patterns
Define Complementary Domains of Neuroepithelium in the Developing CNS
and Are Correlated with Regions Expressing Notch Ligands
Qiufu Ma1,
Lukas Sommer1,
Peter Cserjesi2, and
David J. Anderson1
1 Division of Biology 216-76, Howard Hughes
Medical Institute, California Institute of Technology, Pasadena,
California 91125, and 2 Department of Anatomy and Cell
Biology, College of Physicians and Surgeons of Columbia University,
New York, New York 10032
 ABSTRACT
- INTRODUCTION
- MATERIALS AND METHODS
- RESULTS
- DISCUSSION
- FOOTNOTES
- REFERENCES
ABSTRACT 
Genetic studies in Drosophila and in vertebrates
have implicated basic helix-loop-helix (bHLH) genes in neuronal fate
determination and cell type specification. We have compared directly
the expression of Mash1 and neurogenin1
(ngn1), two bHLH genes that are expressed specifically at early stages of neurogenesis. In the PNS these genes
are expressed in complementary autonomic and sensory lineages. In the
CNS in situ hybridization to serial sections and
double-labeling experiments indicate that Mash1 and
ngn1 are expressed in adjacent and nonoverlapping
regions of the neuroepithelium that correspond to future functionally
distinct areas of the brain. We also showed that in the PNS several
other bHLH genes exhibit similar lineal restriction, as do
ngn1 and Mash1, suggesting that
complementary cascades of bHLH factors are involved in PNS development.
Finally, we found that there is a close association between expression of ngn1 and Mash1 and that of two Notch
ligands. These observations suggest a basic plan for vertebrate
neurogenesis whereby regionalization of the neuroepithelium is followed
by activation of a relatively small number of bHLH genes, which are
used repeatedly in complementary domains to promote neural
determination and differentiation.
Key words:
bHLH proteins;
Mash1;
neurogenins;
Notch ligands;
neurogenesis;
cell lineage
INTRODUCTION
Central questions in developmental neurobiology
include understanding how the nervous system is patterned into
functionally distinct areas and how cellular diversity is generated
within these areas. These questions have been addressed, using genetic analysis in the fruit fly Drosophila. Several important
concepts have emerged from this system. First, proneural genes such as achaete-scute (ac-sc) and atonal,
which encode transcription factors of the basic helix-loop-helix (bHLH)
type, function as neural determination genes (Jan and Jan, 1993 ) (for
review, see Weintraub, 1993). Second, distinct proneural genes are used
in different neuronal sublineages. For example, ac-sc is
essential for external sensory organ formation, whereas
atonal is required for that of chordotonal organs (Jan and
Jan, 1994). Moreover, ectopic expression of as-sc in the
wing disk promotes external sensory organ formation (Rodriguez et al.,
1990; Brand et al., 1993), whereas that of atonal promotes
chordotonal but not external organ formation (Jarman et al., 1993).
Thus, proneural genes play a critical role not only in the choice of
neural fate but also in the choice of neuronal subtype.
The functional characterization of vertebrate homologs of
Drosophila proneural genes has suggested that the principles
described above may be applicable to mammalian neurogenesis as well.
For example, the mammalian ac-sc homolog 1 (Mash1) (Johnson et al., 1990) is expressed in subsets of
neuronal precursors in both the PNS and CNS (Lo et al., 1991; Guillemot
and Joyner, 1993; Guillemot et al., 1993). Within the PNS
Mash1 expression is restricted to autonomic progenitors (Lo
et al., 1991). More recently, we have shown that a novel
atonal-related gene, neurogenin (now called ngn1), is, conversely, expressed in sensory but not
autonomic ganglia in the PNS (Ma et al., 1996). Thus, just as the
proneural genes ac-sc and ato define distinct
neuronal sublineages in Drosophila, Mash1, and
ngn1 define two major neuronal sublineages within the mammalian PNS.
To obtain further insights into the functions of Mash1 and
ngn1 in the CNS as well as the PNS, we have compared
directly the expression patterns of ngn1, Mash1,
and several other genes by single-color or double-color in
situ hybridization to adjacent sections. We find that in many
embryonic CNS regions ngn1 and Mash1 are
expressed in complementary domains that exhibit adjacent and
nonoverlapping boundaries, suggesting that they are involved in the
development of distinct neuronal populations. Within the PNS, moreover,
lineages expressing either ngn1 or Mash1
subsequently express other bHLH genes, such as NSCL1 and
eHAND with similar lineal restrictions, suggesting that
different classes of peripheral neurons may be specified by
complementary cascades of bHLH proteins. Finally, in the CNS,
expression of ngn1 and Mash1 is associated closely with that of two vertebrate Notch ligands, Delta-1
(Dll-1) (Bettenhausen et al., 1995) and/or Jagged
(Lindsell et al., 1995). This overlap is consistent with a potential
functional interaction between these two sets of proteins during
neuronal fate determination, as demonstrated for their homologs in
Drosophila and Xenopus (Ghysen et al., 1993;
Chitnis and Kintner, 1996; Ma et al., 1996).
MATERIALS AND METHODS
In situ hybridization. Digoxigenin-labeled
in situ hybridization was performed as previously described
(Groves et al., 1994) with the following probes: ngn1 (Ma et
al., 1996), Mash1 (Lo et al., 1991), Dll-1 (from
Domingos Henrique), Jagged (Lindsell et al., 1995),
eHAND (Cserjesi et al., 1995), and NSCL1 (Begley
et al., 1992). For double-color in situ hybridization
ngn1 and Dll-1 were labeled with
digoxigenin-UTP (Boehringer Mannheim, Indianapolis, IN), whereas
Mash1 and Jagged were labeled with
fluorescein-UTP (Boehringer Mannheim). A detailed procedure is
available on request.
RESULTS
Complementary cascades of bHLH gene expression in the PNS
Previously, we reported in separate studies that MASH1 protein is
expressed in peripheral autonomic but not sensory ganglia (Lo et al.,
1991) and that ngn1 mRNA is expressed, conversely, in early
sensory but not autonomic ganglia (Ma et al., 1996). To confirm this
apparent mutual exclusivity of expression in the PNS, we performed a
series of in situ hybridization experiments with
Mash1 and ngn1 probes on adjacent serial sections
of rat embryos of various ages. At embryonic day (E) 13.5, ngn1 mRNA was detected in a subset of cells in the
dorsomedial margins of the DRG (Fig.
1A, arrowheads), whereas no
Mash1 transcripts were detected in this region (Fig.
1B, arrowheads). Conversely, at E12.5
Mash1 mRNA was detected easily in forming sympathetic and enteric ganglia (Fig. 1D, large and
small arrowheads, respectively), whereas no ngn1
mRNA was detectable in this region on adjacent sections (Fig.
1C). Similar observations were made in embryos of other ages
(data not shown), indicating that this apparent reciprocity is not a
function of developmental stage. The mutual exclusivity of expression
in the PNS extended to cranial sensory ganglia; ngn1 mRNA
was detected in trigeminal ganglia (Fig. 2C, TG), the otic epithelium (small arrow), and the
acoustic component of the facio-acoustic complex (large
arrow), whereas none of these structures expressed
Mash1 (Fig. 2D).
Fig. 1.
Complementary expression of ngn1
and Mash1 during development of the PNS. Shown are
adjacent transverse sections through the trunk region of E13.5
(A, B) or E12.5
(C, D) rat embryos. ngn1 is expressed in DRG (A,
arrowhead) in which Mash1 is not
expressed (B, arrowhead).
Conversely, Mash1 is expressed in sympathetic ganglia
adjacent to the dorsal aorta (da) (D,
large arrowheads) and enteric ganglia (gut,
g) (D, small
arrowhead), none of which express ngn1
(C). Mutual exclusivity between
Mash1 and ngn1 also is observed in the
ventricular zone of the spinal cord (A,
B; see also Fig. 4).
[View Larger Version of this Image (118K GIF file)]
Fig. 2.
Mutual exclusivity of ngn1 and
Mash1 expression in forebrain and cranial sensory
ganglia. Transverse sections through the developing olfactory lobe
(A, B, in high magnification) and the diencephalon (C, D) of an E14.5 rat
embryo. ngn1 is expressed in the dorsal/rostral side of
the olfactory lobe (A), whereas Mash1 is
expressed in the ventral/caudal side (B).
Mash1 is expressed throughout the hypothalamus
(hyp) and the thalamus (tha) except for a
narrow region (D) in which ngn1 is
expressed (C, arrowheads). ngn1 is expressed in the trigeminal ganglion
(C, TG), the acoustic component of the
facio-acoustic complex (C, large arrow),
and the otic epithelium (C, small arrow),
none of which express Mash1 (D).
Expression of neurogenin1 in these cranial ganglia is
much stronger in younger embryos (Sommer et al., 1996).
[View Larger Version of this Image (118K GIF file)]
Several other bHLH genes have been isolated that exhibit complementary
expression in the PNS similar to that observed for Mash1 and
ngn1. For example, NSCL1 and NSCL2,
both related to the lymphoid-specific gene SCL (Porcher et
al., 1996), were reported to be expressed in sensory but not autonomic
ganglia (Begley et al., 1992; Göbel et al., 1992), as was
NeuroD (Lee et al., 1995); eHAND/Thing1/Hxt
(hereafter referred to as eHAND) was, conversely, reported
to be expressed in autonomic but not sensory ganglia (as well as in
smooth muscle) (Cross et al., 1995; Cserjesi et al., 1995; Hollenberg
et al., 1995). These observations raised the question of the temporal
relationship between expression of these other bHLH genes and that of
Mash1 and ngn1.
In trunk sensory ganglia early expression of both ngn1 and
NSCL1 expression is detected at E11.5 (Fig.
3A,B,
arrowheads). However, at this age, expression of the former
gene is stronger and is detected in more cells than that of the latter
(compare Fig. 3A,B). Conversely, at
E12.5 expression of ngn1 has begun to decline (Fig.
3C, arrowheads), whereas that of NSCL1
has increased (Fig. 3D, arrowheads). These data
suggest that expression of NSCL1 follows or persists longer
than that of ngn1. In support of the former interpretation,
ngn1 mRNA at E12.5 is expressed most strongly in cells at
the dorsomedial margins of the ganglia in which precursors are located;
conversely, NSCL1 mRNA is expressed strongly in interior regions of the ganglia in which differentiated neurons are present (compare Fig. 3D). These data suggest that ngn1
expression precedes that of NSCL1 during sensory
neurogenesis. In the CNS, ngn1 expression also precedes that
of NeuroD (Ma et al., 1996; Sommer et al., 1996). In the
PNS, however, we did not observe a temporal difference between
ngn1 and NeuroD expression during early stages of
DRG development (data not shown). Therefore, NSCL1 seems to
be the latest expressed of the three bHLH genes we examined during
sensory neurogenesis.
Fig. 3.
Lineage-specific bHLH cascades within the PNS.
Both ngn1 and NSCL1 are expressed in rat
DRG at E11.5 and E12.5 (A-D,
arrowheads). NSCL1 expression is
relatively weak at E11.5 (B, arrowheads)
but strong at E12.5 (D, arrowheads).
ngn1 expression at E12.5 has begun to fade in the
ventral half of the DRG (C, arrowheads). Expression of NSCL1 is displaced more laterally from the
ventricular zone (D, arrow) than that of
ngn1 (C, arrow).
eHAND is expressed in the sympathetic ganglia of E10.5
mouse embryo (E, arrowheads) but not in
the sensory ganglia (E, arrows).
Expression of eHAND in the sympathetic ganglia is
undetectable in Mash1 knock-out mice of similar age
(F).
[View Larger Version of this Image (106K GIF file)]
In the case of autonomic ganglia, we wished to know the relationship
between the expression of eHAND and that of
Mash1. However, we were unable to detect any temporal
separation between the expression of these two bHLH genes in
sympathetic ganglia (Fig. 3E; data not shown). Therefore, to
ask whether expression of eHAND is dependent on
Mash1 function, we examined its expression in
Mash1 knock-out mice (Guillemot et al., 1993). No
eHAND mRNA was detected in the sympathetic anlagen of these
mutant embryos (Fig. 3F). This does not simply
reflect an absence of neural crest-derived cells from these ganglion
primordia, however, because we have shown previously that immature
sympathetic neuron precursors are present in such mutant embryos
(Sommer et al., 1995). These data, therefore, indicate that in
autonomic ganglia eHAND expression requires that of
Mash1. This, in turn, suggests that eHAND is
expressed either downstream of, or cross-regulated by, MASH1. However,
Mash1 expression is not sufficient for expression of
eHAND, as seen in the dorsal spinal cord where
Mash1, but not eHAND, is expressed (compare Figs.
1B, 3E).
Mutually exclusive domains of Mash1 and
ngn1 expression in the CNS
The foregoing observations of mutually exclusive bHLH gene
expression in the PNS raised the question of whether this was true in
the CNS as well. As detailed below, the results indicate that expression of Mash1 and ngn1 subdivides many
regions of the ventricular zone into adjacent and nonoverlapping
domains. At E13.5, for example, ngn1 is expressed in two
zones that run the length of the spinal cord, a thin one close to the
roof plate and a broad one in the ventral half (Fig.
1A). Mash1, conversely, appears to be
expressed between these two ngn1 stripes (Fig.
1B). Double-label in situ hybridization to
sagittal sections (passing through the ventricular zone of the spinal
cord) indicated that the boundaries of Mash1 and
ngn1 expression are adjacent and nonoverlapping (Fig.
4B). The combined expression of
Mash1 and ngn1 accounts for essentially the
entire ventricular zone of the spinal cord, with the exception of a
small dorsal region in which Math1 is expressed (Akazawa et
al., 1995) and the floorplate.
Fig. 4.
Mutually exclusive expression of
Mash1 and ngn1 in spinal cord and
forebrain of E14.5 rat embryos demonstrated by double-label in
situ hybridization. Shown are sagittal sections of forebrain (A) and spinal cord (B); rostral is to
the right, and dorsal is to the top in
A and B. B, The section
was cut through the ventricular zone, just lateral to the central
canal. ngn1 expression is visualized with the
purple chromogen and Mash1 expression
with the brown. A, The borders between
ngn1 and Mash1 expression are indicated by arrowheads. ngn1 is expressed in the
presumptive cortex (ctx), and Mash1 is
expressed in the striatum (str). Complementarity also is
seen in optic vesicle (ov). Mash1 and
ngn1 are expressed in a partially overlapping manner in
the olfactory epithelium (arrow; see also Fig. 5).
B, The boundaries between Mash1 and ngn1 expression are adjacent and nonoverlapping.
C, Sagittal section through spinal cord adjacent to that
shown in B, double-labeled with probes for
Jagged (brown) and Dll-1
(purple). Double arrowheads demarcate the top stripe of Jagged mRNA
expression (compare Fig. 6B,
arrow), and double arrows demarcate the
bottom stripe (compare Fig. 6B,
arrowhead). The top stripe of Jagged mRNA
(double arrowheads) partially overlaps the ventral
boundary of the major dorsal Dll-1 expression domain
(compare Fig. 6D, arrow), although
it is not possible to determine at this level of resolution whether
individual cells coexpress both genes. The ventral stripe of
Jagged mRNA (compare Fig. 6B,
arrowhead) appears perfectly interdigitated between the
two stripes of Dll-1 mRNA (compare Fig.
6D, arrow and
arrowhead). Note that the boundaries of
Jagged and Dll-1 do not correspond to
those of Mash1 and ngn1; however,
Jagged is expressed only in the
ngn1-expressing region (see also Fig. 6).
[View Larger Version of this Image (111K GIF file)]
Similarly, in the telencephalon, Mash1 is expressed in the
presumptive basal ganglia (Fig. 4A, str),
whereas ngn1 is expressed in the presumptive cortex
(ctx), as is the related gene ngn2 (Gradwohl et
al., 1996; Sommer et al., 1996). Double labeling again revealed that
the boundaries between the telencephalic expression domains of
ngn1 and Mash1 are adjacent and nonoverlapping
(Fig. 4A, arrowheads). A similar mutual
exclusivity was observed elsewhere in the forebrain. For example,
within the prospective olfactory lobes, ngn1 is expressed in
the dorsal part (Fig. 2A), whereas Mash1
mRNA is detected in the ventral regions (Fig. 2B). In
the diencephalon Mash1 is expressed throughout the
ventricular zone, with the exception of a small region (Fig.
2D, arrowheads) in which ngn1
is expressed instead (Fig. 2C). Such mutual exclusivity also
is seen within the optic vesicle (Fig. 4A,
arrowhead and ov).
In addition to this striking complementarity of Mash1
and ngn1 expression, we also observed some CNS regions that
express both genes, including the olfactory epithelium (Fig.
5A,B), midbrain (Fig. 5C,D), and (at early stages
(E11.5-E12.5)) the ventral spinal cord (data not shown). Within these
regions of overlap, differences in the expression pattern of the two
genes are, nevertheless, evident. For example, in the E14.5 olfactory
epithelium, ngn1 expression is restricted to cells located
in the basal layer (Fig. 5A), whereas Mash1 is
expressed in cells that span the epithelium (Fig. 5B). In
the midbrain the domain of highest ngn1 expression appears
displaced laterally from the ventricular wall, whereas that of
Mash1 fills the entire ventricular zone (compare Fig. 5C,D). Moreover, expression of
Mash1 appears relatively uniform (Fig. 5D),
whereas that of ngn1 is restricted to a subset of cells (Fig. 5C).
Fig. 5.
Overlapping but sequential expression of
ngn1 and Mash1. Transverse sections
through the olfactory epithelium (A,
B) and sagittal sections through the midbrain region
(C, D) of an E14.5 rat embryo are
illustrated. ngn1 is expressed in cells located in the
basal layer of the olfactory epithelium (A,
arrowhead), whereas Mash1 is expressed in
cells spanning the epithelium (B). In the midbrain ngn1 expression is scattered (C), whereas
that of Mash1 is much more uniform (D).
Also, ngn1 expression (but not that of
Mash1) is displaced laterally from the ventricular wall
(C, D).
[View Larger Version of this Image (121K GIF file)]
Relationship of Mash1 and ngn1 expression
to that of Delta and Jagged
In Drosophila the proneural genes ac-sc both
activate expression of the lateral inhibitory signal Delta
and are, in turn, repressed by signaling through Notch, a receptor for
Delta (Ghysen et al., 1993). Similarly, in Xenopus
X-ngnr-1 activates expression of X-Delta-1 and is
negatively regulated by signaling through X-Notch-1 (Ma et al., 1996).
Recently, two mammalian Notch ligands, Dll-1 and
Jagged, have been identified (Bettenhausen et al., 1995; Lindsell et al., 1995). To determine whether MASH1 and/or Neurogenin1 similarly might activate expression of these Notch ligands in mammals,
we compared their expression with that of Dll-1 and
Jagged.
In the spinal cord at E13.5, Jagged is expressed primarily
in the ventral region in several narrow longitudinal (i.e.,
rostrocaudal) stripes that appear as bands across the ventricular zone
in transverse sections (Fig. 6B,
arrow; see also Lindsell et al., 1995). Comparison of
adjacent sections indicates that these bands lie within the region in
which ngn1 also is expressed (compare Fig.
6A,B; see also Fig.
4B,C). Moreover, the top band of
Jagged mRNA expression (Fig. 6B,
arrow) appears well correlated with the dorsal boundary of
the band of ngn1 expression (Fig. 6A,
arrow). In contrast to Jagged, Dll-1
is expressed primarily in the prospective alar (dorsal) region of the
spinal cord (Fig. 6D; see also Bettenhausen et al., 1995; Lindsell et al., 1996) in a domain that encompasses the entire
band of Mash1 expression (Figs. 4C,
6C). Double-label in situ hybridization confirms
that some boundaries of Jagged and Dll-1
expression, like those of Mash1 and ngn1, are
mutually exclusive (Fig. 4C, arrows), confirming
previous observations made in rat (Lindsell et al., 1996) and chick
(Myat et al., 1996). However, the dorsal stripe of Jagged
expression (Fig. 6B, arrow) overlaps the
ventral boundary of Dll-1 expression (Fig.
6D, arrow), as confirmed by
double-labeling on sagittal sections (Fig. 4C,
arrowheads), so that the complementarity of Notch ligand
expression in the spinal cord is not perfect.
Fig. 6.
Comparisons of Mash1 and
ngn1 expression to that of Dll-1 and
Jagged. Adjacent transverse trunk sections of E13.5
(A-D) and sagittal sections
through the medulla and pons of E14.5
(E-H) rat embryos are
illustrated. The dorsal boundary of the Jagged stripe
(B, arrow) seems to correspond to the
dorsal boundary of the ventral ngn1 expression domain
(A, arrow). The dorsal
Dll-1 expression domain (D) encompasses
that of Mash1 (C) and extends both
dorsally to the region expressing the dorsal ngn1 stripe (A, arrowhead) and ventrally into
the area corresponding to the top part of the ventral
ngn1 stripe (A). In the medulla
(mdl) and pons (pons),
complementarity between ngn1 and Mash1 is
indicated by the arrows (E,
G). Expression of Jagged is
restricted to the region in which ngn1 is strongly
expressed (F), whereas Dll-1 is
expressed throughout the ventricular zone (H).
Jagged expression in this region is discontinuous
(F, arrowheads), as in the spinal cord
(B).
[View Larger Version of this Image (124K GIF file)]
Although both Mash1 and ngn1 and
Jagged and Dll-1 exhibit complementary boundaries
of expression in the spinal cord, comparison of adjacent sections
indicates that these boundaries are located in distinct regions. For
example, Dll-1 expression (Fig. 6D)
extends dorsally past the top boundary of the Mash1 band
(Fig. 6C) to encompass the thin stripe of ngn1
expression adjacent to the roof plate (Fig. 6A,
arrowhead; compare Fig. 4B vs
C). Furthermore, the ventral boundary of Dll-1
expression (Fig. 6D, arrow) overlaps the
top part of the ventral band of ngn1 expression (Fig.
6A, arrow). Thus, expression of
Dll-1 is detected in both Mash1- and ngn1-expressing regions. Interestingly, however,
Jagged expression is detected only in regions that express
ngn1 (compare Fig. 6A vs
B).
The correlation between Jagged and ngn1
expression observed in the spinal cord seems to extend to other regions
of the CNS. For example, in the ventricular zone of the medulla and
pons Jagged expression is restricted primarily to the region
that also expresses high levels of ngn1 (compare Fig.
6E vs F). By contrast, in this brainstem region Dll-1 is expressed in a pattern that
overlaps the expression domains of both Mash1 and
ngn1 (compare Fig. 6H vs
E,G). Similarly, in the
telencephalon strong Dll-1 expression is found in both the
striatum, which expresses Mash1, and in the cortex, which
expresses ngn1 (Lindsell et al., 1996) (data not shown). By
contrast, strong expression of Jagged in the brain is
observed only in regions in which ngn1 (or ngn2;
Gradwohl et al., 1996; Sommer et al., 1996) is strongly expressed,
although faint expression can be seen in some regions that only express Mash1 (such as in the striatum). Thus, a generalization that
emerges from these studies is that in the CNS Jagged
expression is associated primarily with that of ngn1,
whereas Dll-1 expression can be associated with that of
either ngn1 or of Mash1.
DISCUSSION
Mutual exclusivity of Mash1 and neurogenins
expression during mammalian neurogenesis
The most striking finding to emerge from the present studies is
that Mash1 and ngn1 are expressed in
complementary domains, which exhibit adjacent and nonoverlapping
boundaries, in many regions of the CNS. In several regions of the CNS
the complementary domains delineated by Mash1 and
ngn1 expression correspond to future functional
subdivisions: in the spinal cord to the alar and basal regions and in
the forebrain to the cortex and striatum. This mutual exclusivity
mirrors the complementarity of expression of these bHLH genes in the
PNS, in which Mash1 is expressed by autonomic and
ngn1 by sensory progenitors.
Recently, we reported the isolation of two other
ngn1-related genes, ngn2 and ngn3
(Sommer et al., 1996). In the PNS ngn2 also is restricted to
sensory lineages, such as in DRG and several epibranchial
placode-derived ganglia in which Mash1 is not expressed (Sommer et al., 1996). In the CNS, particularly in the forebrain region, expression of ngn2 (also known as Math4A;
Gradwohl et al., 1996) shows a similar regional restriction like that
of ngn1 (Sommer et al., 1996) and appears complementary to
that of Mash1 (Gradwohl et al., 1996). By contrast,
ngn3 is expressed only in extremely restricted regions of
the CNS. For example, in the spinal cord ngn3 expression is
restricted to the region close to the floorplate (Sommer et al., 1996).
Thus, much of the developing CNS can be divided into regions that
express either Mash1 or one or more of the
ngns.
In the PNS the complementary expression of Mash1 and the
ngns appears to be reflected in the expression of several
additional bHLH genes that may serve as potential downstream targets.
Expression of NeuroD (Lee et al., 1995; Ma et al., 1996;
Sommer et al., 1996) and NSCL1 (Begley et al., 1992) (Fig.
3C,D) is restricted to the sensory
lineage, whereas eHAND expression is restricted to autonomic lineages (Cserjesi et al., 1995). The finding that Mash1 function is
necessary for expression of eHAND in sympathetic ganglia
indicates that eHAND is likely a direct or an indirect target of Mash1. In Xenopus a homolog of the ngns,
X-ngnr-1, activates expression of X-NeuroD
in a unidirectional cascade during primary neurogenesis (Ma et al.,
1996). Similarly, X-NeuroD has been shown to activate expression of Xenopus NSCL (J. Lee, personal communication).
Our in situ data (Fig. 2A-D;
Sommer et al., 1996) are consistent with the idea that the
ngns, neuroD, and NSCL1 may function
in cascade during sensory neurogenesis in higher vertebrates, as well.
Confirmation of this will, however, await loss-of-function analyses in
ngn1 and/or ngn2 knock-out mice.
Functional significance of complementary bHLH gene expression
during neurogenesis
Why are different classes of bHLH genes used to promote
neurogenesis in different regions of the CNS and PNS? The answer to this question is likely to relate to differences in the functions of
these genes. In the Drosophila PNS, atonal (which
is structurally related to the ngns) is required for
development of chordotonal organs, whereas achaete-scute is
required for that of external sensory (es) organs (Jan and Jan, 1994).
These genes are not functionally interchangeable, and recent data
indicate that the key amino acid residues responsible for these
functional differences lie in the basic region and likely mediate
protein-protein rather than protein-DNA interactions (Chien et al.,
1996). Thus in Drosophila structural differences among
different neural bHLH proteins account for their ability to promote the
determination of particular neural cell types, and the same is likely
to be true in vertebrates. The noninterchangeable functions of
different classes of neural bHLH proteins indicate that the choice of a
neural (or neuronal) fate is coupled to the specification of a
particular cell identity from the earliest developmental stages.
However, a given bHLH gene is not sufficient to specify a particular
neural cell type, because in both Drosophila and vertebrates
individual bHLH genes are required for the development of more than one
class of neurons. A single bHLH gene is, therefore, likely to act in
combination with other region-specific transcriptional regulators in
the pathways that determine neuronal identities. This would explain
why, for example, expression of Mash1 is followed by that of
eHAND in the PNS, but not the CNS.
Overlapping expression of Mash1
and ngns
Although spatial complementarity between expression of
Mash1 and ngns seems to be the rule in most parts
of the CNS, there are some regions in which these genes are
coexpressed. For example, Mash1, ngn1, and
ngn2 all are expressed in the midbrain region (Fig.
5C,D; data not shown). Other sites of
ngn1 and Mash1 coexpression include the olfactory
epithelium and midbrain. Interestingly, within these overlapping
regions differences in the expression of these genes are clearly seen.
For example, in the olfactory epithelium ngn1 expression is
restricted to the basal layer, whereas Mash1 expression
spans the epithelium. Conversely, in the midbrain Mash1 is
expressed in the ventricular zone, whereas both ngn1 and
ngn2 are displaced slightly lateral to this region (Fig.
5C,D; data not shown). These differences
suggest that even in these regions of overlap these genes may function
at different developmental stages in the same cells or in distinct but
intermingled groups of cells that develop on different schedules.
Relationship of bHLH gene expression to that of Notch ligands
Previously, it has been shown that the Notch ligands
c-Delta-1 and c-Serrate-1 (a chick homolog of
Jagged) and Delta-1 (Dll-1) and
Jagged (Lindsell et al., 1996; Myat et al., 1996) exhibit complementary domains of expression in the spinal cord of chick and
rat, respectively. In the chick this complementarity seems perfect. Our
data indicate that it is partially lost in rat, however (Fig. 6).
Because Jagged and Dll-1 are both ligands for
Notch, they may be functionally equivalent. In that case, there would be little selection pressure to maintain such perfect complementarity. The bHLH genes Mash1 and ngn1 also exhibit
complementary boundaries of expression in the rodent spinal cord. In
the fly and the frog, homologs of these genes are demonstrably not
functionally equivalent (Chien et al., 1996; Chitnis and Kintner, 1996;
Ma et al., 1996). There may, therefore, be more selection pressure to
maintain the complementarity of bHLH gene expression within the CNS.
Analysis of the expression patterns of the chick homologs of these
genes should be informative in this respect.
The side-by-side comparison of bHLH and Notch ligand gene expression
presented here indicates that the boundaries of Jagged and
Dll-1 expression do not correspond precisely to the
boundaries between the domains of Mash1 and ngn1
expression (Figs. 4B,C, 6).
Specifically, Dll-1 is expressed in domains expressing
either Mash1 or ngn1. On the other hand,
high-level Jagged expression usually is (but not always)
associated with that of ngn1. If, indeed, Jagged
and Dll-1 are functionally equivalent, it is not clear why
expression of Jagged should be associated preferentially with that of ngn1. This apparent linkage may reflect
regulatory rather than functional constraints on the two genes.
The fact that the expression of the bHLH genes and that of the Notch
ligands overlaps in the ventricular zone in both space and time raises
the possibility that there is a regulatory interaction between these
proteins in higher vertebrates, similar to that which occurs in
Drosophila and Xenopus (Chitnis et al., 1995; Chitnis and Kintner, 1996; Ma et al., 1996) (for review, see Lewis, 1996). Specifically, proneural genes in the fly and X-ngnr-1
in the frog have been shown to activate expression of Delta
and its Xenopus homolog, X-Delta-1, respectively.
Our data are compatible with the idea that such an activation occurs in
rodents as well, as suggested previously (Kunisch et al., 1994) (for
review, see Lewis, 1996). Nevertheless, in Mash1 knock-out
mice, expression of Dll-1 and Jagged in the CNS
is not affected (our unpublished results), consistent with the failure
to detect any other phenotypic defects in the CNS of these embryos
(Guillemot et al., 1993). This may reflect functional redundancy or
compensation between Mash1 and other unrelated bHLH genes;
alternatively, Notch ligands may not be regulated by Mash1
in mice. Similarly, in the case of ngn1 and ngn2,
the overlap in their CNS expression may obscure defects in Notch ligand
expression in single knock-out mice. Analysis of mice containing
targeted mutations in both genes should, however, be informative.
FOOTNOTES
Received Dec. 20, 1996; revised Feb. 19, 1997; accepted March 6, 1997.
Q.M. and L.S. are Associates of the Howard Hughes Medical Institute;
D.J.A. is an Investigator of the Howard Hughes Medical Institute. We
are grateful to Gerry Weinmaster for providing the Jagged probe, to Domingos Henrique for the mouse
Dll-1 probe, to Richard Baer for the mouse
NSCL1 probe, to Eric Olson and two anonymous reviewers
for their helpful comments, and to Tetsu Saito for the double-label
in situ hybridization protocol.
Correspondence should be addressed to Dr. David J. Anderson at the
above address.
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