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Mutations in the Notch Pathway Alter the Patterning of Multifidus.

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THE ANATOMICAL RECORD 295:32–39 (2012)
Mutations in the Notch Pathway Alter
the Patterning of Multifidus
REBECCA E. FISHER,1,2* HEATHER F. SMITH,1 KENRO KUSUMI,2
ERICA E. TASSONE,2 ALAN RAWLS,2 AND JEANNE WILSON-RAWLS2
1
Department of Basic Medical Sciences, The University of Arizona College of
Medicine–Phoenix, Phoenix, Arizona
2
School of Life Sciences, Arizona State University, Tempe, Arizona
ABSTRACT
Clinical studies have suggested that defects in the epaxial muscles,
particularly multifidus, may contribute to the etiology of idiopathic scoliosis. While the epaxial muscles and the vertebrae derive from the same
embryonic segmentation process, the mechanisms that pattern the multisegmental back muscles are still unclear. The process of segmentation is
regulated by the Notch signaling pathway, and mutations in the modulators delta-like 3 (Dll3) and lunatic fringe (Lfng) are genetic models for
spinal disorders such as scoliosis. Osteological defects have been characterized in these genetic models, but myological phenotypes have not previously been studied. We analyzed the multifidus muscle in the mouse
(Mus musculus) and observed intriguing changes in the cranio-caudal
borders of multifidus in Dll3 and Lfng models. Statistical analysis did not
find a significant association between the majority of the multifidus
anomalies and the vertebral defects, suggesting a previously unappreciated role for Notch signaling in patterning epaxial muscle groups. These
findings indicate an additional mechanism by which DLL3 and LFNG
may play a role in the etiology of human idiopathic scoliosis. Anat Rec,
C 2011 Wiley Periodicals, Inc.
295:32–39, 2012. V
Key words: idiopathic scoliosis;
fringe; delta-like 3
The vertebral column is composed of alternating vertebrae and intervertebral discs that are supported by spinal ligaments and the paravertebral musculature. All of
these tissues are derived from somites, clusters of paraxial mesoderm that are deposited in a metameric pattern on either side of the neural tube early in
development. Each somite differentiates into four cell
lineage-specific compartments, including the sclerotome
(vertebrae and ribs), syndetome (axial tendons), myotome (axial skeletal muscle), and dermomyotome (dermis
and skeletal muscle progenitor cells). As each of these
compartments give rise to key elements of the spine, disruptions of somite differentiation may result in debilitating spinal defects.
The importance of properly coordinated spinal development is underscored in patients with scoliosis. Scoliosis affects up to 3% of the general population and is
defined by the presence of a lateral curvature of greater
than 10 (reviewed in Kusumi and Turnpenny, 2007;
Alman, 2010). In actuality, scoliosis is often a complex,
C 2011 WILEY PERIODICALS, INC.
V
multifidus;
Notch; lunatic
three-dimensional defect with deformation occurring in
the frontal and sagittal planes along with a rotational
component (Meier et al., 1997). Congenital scoliosis is
Grant sponsor: NIH-NIAMS; Grant number: RO1 AR050687;
Grant sponsor: Hitchings-Elion Fellowship; Grant number:
1000336.01.
*Correspondence to: Rebecca E. Fisher, PhD, Department of
Basic Medical Sciences, The University of Arizona College of
Medicine-Phoenix, 550 East Van Buren Street, Phoenix, AZ
85004. Fax: 602 827-2212. E-mail: rfisher@email.arizona.edu
Rebecca E. Fisher and Heather F. Smith contributed equally
to this work.
Heather F. Smith is currently affiliated with Department of
Anatomy, Arizona College of Osteopathic Medicine, Midwestern
University, Glendale, AZ 85308.
Received 20 May 2011; Accepted 9 August 2011
DOI 10.1002/ar.21488
Published online 18 November 2011 in Wiley Online Library
(wileyonlinelibrary.com).
MULTIFIDUS DEFECTS IN NOTCH PATHWAY MUTANTS
33
Fig. 1. The epaxial muscles of the back. (A) On the left, the splenius muscles; on the right, the erector
spinae muscles, including iliocostalis, longissimus, and spinalis. (B) On the left, the transversospinalis
muscles, including semispinalis, multifidus, and rotatores; on the right, the levatores costarum, intertransversarii, and interspinales muscles. Drawing by Brent Adrian.
difficult to manage clinically, as the curves are resistant
to correction and tend to progress into debilitating
deformities (McMaster, 2001). Malformation of the vertebrae can produce the lateral curvatures of congenital
scoliosis (Erol et al., 2004). However, the majority of scoliosis deformities are classified as ‘‘idiopathic,’’ with an
unknown etiology. Gao et al. (2007) found that 2%–3% of
school-aged children have idiopathic scoliosis. In these
cases, it is possible that disruptions of the paravertebral
musculature could result in decreased stability of the
vertebral column, and increased lateral flexion and rotation of the spine.
Stabilization and movements of the vertebral column
are dependent on the precise patterning of paravertebral
muscles and their attachments to skeletal elements
through tendons. In tetrapods, the paravertebral musculature is arranged in a series of longitudinal columns,
innervated by the dorsal rami of spinal nerves. These
muscles are divided into four layers in humans, including a superficial splenius layer, the erector spinae, the
transversospinalis, and a deep layer including the levatores costarum, intertransversarii, and interspinales
(Fig. 1). The transversospinalis group is itself comprised
of three subdivisions: the semispinalis, rotatores, and
multifidus (Fig. 1B). In cases of idiopathic scoliosis,
structural and electromyographic asymmetry of the paravertebral muscles has been documented (Riddle and
Roaf, 1955; Zuk, 1962; Butterworth and James, 1969;
Spencer and Zorab, 1976; Alexander and Season, 1978;
Yarom and Robin, 1979; Reuber et al., 1983; Sahgal
et al., 1983; Zetterberg et al., 1983; Mannion et al.,
1998), and a number of studies have reported asymmetry in the multifidus muscle in particular (e.g., fiber type
distribution, hypertrophy, atrophy, centralization of
nuclei, and disruption of sarcotubular and myofibrillar
elements; Fidler and Jowett, 1976; Khosla et al., 1980;
Ford et al., 1984; Bylund et al., 1987; Meier et al., 1997;
Chan et al., 1999). Whether this asymmetry is responsible for the initiation of idiopathic scoliosis, its progression, or both, remains unclear.
Currently, little is known about the signals that direct
the patterning of the paravertebral muscles (reviewed in
Rawls and Fisher, 2010). Embryonic muscle masses are
responsive to signals that establish the general body
plan. The best described are the Hox genes, which
impose regional identity along the cranio-caudal axis of
both the body and limbs (Hashimoto et al., 1999; Alvares
et al., 2003). At the level of the limbs, migrating myogenic cells respond to Hox signaling from the surrounding lateral plate mesoderm. In other regions, there is
evidence that Hox genes are able to instruct myoblasts
in a cell autonomous manner (Alvares et al., 2003). The
interplay between signaling factors contributing to dorsoventral and proximodistal pattering in the limb bud,
including FGFs, SHH, and BMPs, also impose identity
on muscle masses (Riddle et al., 1995; Vogel et al.,
1995). The further segregation of muscle masses into
anatomically distinct muscles is dependent on signals
34
FISHER ET AL.
Fig. 2. Lfng and Dll3 mutants display severe vertebral and costal defects.
from neighboring tissue. In the limb, muscle patterning
requires reciprocal interactions with the adjacent tendon
primordial (Kardon, 1998). Additional signals from the
surrounding mesoderm have been described that are dependent on the expression of TCF4 (Grim and Wachtler,
1991; Kardon et al., 2003).
The Notch signaling pathway is a candidate for regulating skeletal muscle patterning. This pathway has
been associated with the regulation of the segmental
clock and the differentiation of skeletal muscle. Genetic
disruptions in the modulators of Notch signaling, lunatic
fringe (Lfng) and delta-like 3 (Dll3), have been shown to
produce severe segmental defects affecting the vertebrae
and ribs in both mouse models and in the autosomal recessive congenital vertebral disorder, spondylocostal dysostosis (Fig. 2; Evrard et al., 1998; Kusumi et al., 1998;
Zhang and Gridley, 1998; Bulman et al., 2000; Dunwoodie et al., 2002; Sparrow et al., 2006). While both mutations produce segmental defects, the effects of
segmentation and vertebral malformations are distinct
due to their differing roles in Notch regulation (reviewed
in Turnpenny, 2010). Both Lfng and Dll3 continue to be
expressed in the rostral and caudal compartments of
somites, respectively, after segmentation, and the significance of this somitic expression is not clear (Dunwoodie
et al., 1997; Aulehla and Johnson, 1999). While studies
have described the osteological malformations due to
Lfng and Dll3 mutations, the effects on the paravertebral musculature have not been reported. We analyzed
the multifidus muscle in the mouse (Mus musculus) and
observed defects due to null mutations in two different
genes in the Notch signaling pathway, Lfng and Dll3.
The observation of global changes in multifidus in both
Lfng and Dll3 mutants suggests a previously unappreciated role for Notch signaling in the patterning of epaxial
muscles.
MATERIALS AND METHODS
Mice
Mouse Dll3pu, Dll3tm1Rbe (referred to as Dll3neo),
Lfngtm1Rjo (null animals referred to as Lfng–/–), C57BL/
6J, and CD1 lines were used for analysis. All animals
were maintained in an AALAC certified facility with
standard light cycles and an ad libitum food and water
regimen under protocols approved by the Institutional
Animal Care and Use Committee at Arizona State University. Dll3neo and Lfngtm1Rjo mutations were maintained on
a C57BL/6J background, having been backcrossed 10 generations or greater onto this strain. Since homozygous
mutants are not viable neonatally on a C57BL/6J background, outcrosses to the CD1 line were required to produce viable adult mutants. Lfngtm1Rjo were also
maintained by intercross with CD1 for viability. Dll3pu
animals were maintained by intercrosses of heterozygous
animals for this inbred line. Homozygous animals were
generated by an intercross of heterozygous carriers. Euthanasia was carried out by carbon dioxide inhalation. Genotype was determined using PCR-based assays, as
described previously (Evrard et al., 1998; Kusumi et al.,
1998; Dunwoodie et al., 2002).
Analysis of Multifidus
While the myology of the laboratory rat (Rattus norvegicus) is well documented (e.g., Hebel and Stromberg,
1976; Brink and Pfaff, 1980; Wingerd, 1988; Chiasson
1994; Walker and Homberger, 1997), detailed muscle
descriptions are largely lacking for the laboratory mouse
(Mus musculus; e.g., Hummel et al., 1975; Cook, 1976;
Feldman and Seely, 1988; Popesko et al., 1992; Komárek,
2004). Origin and insertion data are available for a limited number of paravertebral muscles, including multifidus, but these data are confined to the T12 to L6
vertebral levels and the number of specimens sampled is
relatively small (Cornwall et al., 2010, N ¼ 3; Hesse
et al., 2010, N ¼ 5). As a result, we first examined the
multifidus muscles in 12 wild-type specimens from our
colony of C57BL/6J-CD1 hybrids. We then analyzed littermates who were homozygous null for Lfng and Dll3.
All dissections were carried out bilaterally on adult animals (6–8 weeks) using a Nikon SMZ800 stereodissecting microscope and photodocumented using a Nikon
Coolpix 4500 digital camera. For each specimen, we
noted both the origins and insertions of multifidus, or its
unilateral or bilateral absence.
MULTIFIDUS DEFECTS IN NOTCH PATHWAY MUTANTS
35
Fig. 3. Lfng and Dll3 mutants display anomalous cranial and caudal borders of the multifidus muscle.
Multifidus muscles are shown as left-right paired columns indicating vertebral level. Observations from
each specimen are shown. The arrows indicate the location of the cranial and caudal borders of multifidus in the wild-type condition. Vertebral levels: C, cervical; T, thoracic; L, lumbar.
Analysis of Vertebrae
After the analysis of multifidus was complete, specimens were prepared for osteological analysis by fixation
in ethanol followed by staining with Alizarin Red/Alcian
Blue, as described previously (McLeod, 1980; Kusumi
et al., 1998). In wild-type and mutant specimens, vertebral malformations were assessed at muscle origin and
insertion sites, including the spinous processes, transverse processes, mammillary processes, and cranial and
caudal articular processes. The cervical, thoracic, and
lumbar vertebrae were disarticulated from each other,
and from the cranium and sacrum. The processes of
each vertebra were then visually inspected, and any
defects were recorded. Vertebral malformations were
treated as a dichotomous variable in which defects at
each attachment point were scored as present or absent
for each vertebral level.
Statistical Analyses
A Yates corrected chi-squared (v2) test with the a level
set at 0.05 was conducted to determine whether statistically significant differences exist between the frequencies of multifidus defects in mutant versus wild-type
littermates. This analysis was also conducted separately
for Dll3 and Lfng mutants. Although it has been
reported previously that mutations in the Notch signaling pathway lead to osteological segmentation defects
(Evrard et al., 1998; Kusumi et al., 1998; Zhang and
Gridley, 1998; Dunwoodie et al., 2002), a second chisquared test was performed between the frequencies of
vertebral defects in the mutant and wild-type specimens
to statistically test these observations in the current
sample.
Several statistical tests were conducted using Statistica 4 to assess whether a significant association exists
between the multifidus defects and the vertebral defects.
Two-way analysis of variance (ANOVA) and subsequent
Tukey post hoc comparisons were used to test whether
differences in the levels of vertebral defects exist
between genotypes or multifidus defect category. In this
analysis, multifidus category was treated as a categorical variable with four possible states: normal, reduced,
expanded, or absent. Regression Analyses were also conducted for the cranio-caudal extents of vertebral and
multifidus defects. Significant correlation coefficients (P
< 0.005) were interpreted as evidence of a relationship
between the levels of vertebral defects and the vertebral
levels of defects in multifidus.
RESULTS
In the mouse, the multifidus muscles originate on a
mammillary (lumbar region) or transverse process (thoracic region) and insert onto a spinous process two to
four vertebrae craniad to the site of origin. These
muscles span from the L5 to T2 vertebral levels. In Lfng
mutants, 13/15 specimens displayed multifidus anomalies. Anterograde shifts were observed in both the cranial and caudal borders of this muscle group (Fig. 3).
The most common anomaly was a unilateral or bilateral
anterograde shift of the cranial multifidus border to C2
or C1 rather than T2 (N ¼ 6/15; Figs. 3 and 4). This anterograde shift was associated with the addition of new
muscle segments rather than an increase in muscle fiber
length with novel insertion sites craniad to T2. In addition, the presence of multifidus in the cervical region
was not associated with a reduction or loss of the epaxial
muscles that normally populate this region.
36
FISHER ET AL.
Fig. 4. Comparison of the cranial border of the multifidus muscle
(M) in a wild-type versus mutant Lfng mouse. Note the anterograde
shift to a C2 insertion, compared to the T2 insertion in the wild-type.
All of the other epaxial muscles have been removed from the neck in
these views. Scale bar is 1 mm.
Posterograde shifts of the cranial multifidus border
were also observed bilaterally or unilaterally, with a cranial insertion point at only T6 or T9 rather than T2 (N
¼ 3/15; Fig. 3). In three specimens, both cranial and caudal borders were shifted in an anterograde fashion, with
cranial borders at C2 and caudal borders at T6, T12, or
L1 (N ¼ 3/15; Fig. 3). In one Lfng mutant specimen,
there was a complete bilateral absence of the multifidus
muscle (N ¼ 1/15; Fig. 3). Yates corrected v2 analysis
revealed highly significant differences in the frequency
of multifidus defects in Lfng mutants (v2 ¼ 19.55, P <
0.0001) compared to their wild-type littermates. Significant changes in the cranial border of multifidus were
also observed in Dll3 mutants (Fig. 3; N ¼ 9/12; v2 ¼
13.67, P < 0.0001).
While the developmental processes regulating muscle
and bone formation are clearly distinct, defects in underlying osteological structures could lead to alterations in
muscle attachment sites and patterning. To distinguish
between muscle defects that are secondary to skeletal
anomalies versus those that may arise from a role for
Notch regulation in muscle patterning, we carried out
an osteological analysis on all specimens. Mouse mutations of Lfng and Dll3 have been previously described to
display widespread vertebral and rib defects (Grüneberg,
1961; Evrard et al., 1998; Kusumi et al., 1998; Zhang
and Gridley 1998; Dunwoodie et al., 2002). We confirmed
that defects occur at almost all vertebral levels in Dll3
and Lfng homozygous mutants (Fig. 2). In addition, the
Lfng and Dll3 mutant mice exhibited rib fusions and
bifurcations that led to highly variable intercostal distances. Osteological defects were not observed in any of
12 wild-type littermates analyzed.
In mice, the multifidus muscles course between a
transverse or mammillary process and a spinous process.
If the multifidus border shifts observed in the Lfng and
DII3 mutant mice are secondary to vertebral defects,
then defects in these processes should correspond with
the vertebral levels of myological interruption. The vertebral defects were much more severe in the lumbar
region than in the thoracic and cervical regions in both
the Lfng and Dll3 mutant mice. Though fusions were
observed between vertebrae, the axial level of individual
transverse and spinous processes could be distinguished
in the cervical and thoracic regions. Importantly, the spinous process at T2 was morphologically distinct and consistently present in both mutant strains. A two-way
ANOVA of the vertebral levels of skeletal defects by both
genotype (wild-type, Lfng/, Dll3/) and muscular category (normal, reduced, expanded) revealed no significant differences overall in the level of vertebral defects
among normal, reduced and expanded muscles (P ¼
0.486). However, breaking down the analysis by side and
cranio-caudal extent revealed that for the right caudalmost extent, muscular defect categories (normal,
reduced, expanded, and absent) were significantly different overall (Table 1). Additionally, a regression analysis
between the cranio-caudal extents of the multifidus muscle and vertebral defects revealed a significant correlation between the caudal-most osteological defect and the
caudal-most myological defect in the DII3 mutant mice
(Table 2). However, for the majority of cases, there was
no statistical association between the cranio-caudal borders of the multifidus muscle and defects in its attachment points on the vertebrae.
DISCUSSION
The epaxial muscle groups that span adjacent vertebrae (e.g., rotatores) are derived from individual somite
myotomal compartments. However, when epaxial
muscles span multiple vertebral levels, the cells from
multiple myotomes contribute to individual muscle fibers
(Huang et al., 2000). Studies performed in rat embryos
indicate that these transversospinalis muscles first
TABLE 1. Results of two-way ANOVA and Tukey post hoc tests of the vertebral levels of relevant
osteological defects by both genotype and multifidus defect category
Multifidus defect
categories
Genotypes
Significant Tukey
tests
Right cranial-most
defects
Left cranial-most
defects
Right caudal-most
defects
Left caudal-most
defects
F ¼ 1.482 (P ¼ 0.253)
F ¼ 0.9553 (P ¼ 0.403)
F ¼ 5.70 (P ¼ 0.027)
F ¼ 2.61 (P ¼ 0.122)
F ¼ 6.078 (P ¼ 0.240)
None
F ¼ 3.275 (P ¼ 0.087)
None
F ¼ 2.06 (P ¼ 0.168)
Reduced vs. normal
(P ¼ 0.0138)
F ¼ 1.66 (P ¼ 0.213)
None
Significant correlations are indicated in bold.
37
MULTIFIDUS DEFECTS IN NOTCH PATHWAY MUTANTS
TABLE 2. Results of regression analyses between cranio-caudal levels of relevant vertebral defects and
multifidus border defects
Lfng
Dll3
Overall
Right cranial-most defects
Left cranial-most defects
Right caudal-most defects
Left caudal-most defects
R ¼ 0.450 (P ¼ NSD)
R ¼ 0.0286 (P ¼ NSD)
R ¼ 0.318 (P ¼ NSD)
R ¼ 0.298 (P ¼ NSD)
R ¼ 0.264 (P ¼ NSD)
R ¼ 0.201 (P ¼ NSD)
R ¼ 0.180 (P ¼ NSD)
R ¼ 1.000 (P < 0.05)
R ¼ 0.296 (P ¼ NSD)
R ¼ 0.210 (P ¼ NSD)
R ¼ 1.000 (P < 0.05)
R ¼ 0.325 (P ¼ NSD)
Significant correlations are indicated in bold. NSD, no significant difference.
Fig. 5. Summary of mouse axial phenotypes characterized in Hox single gene and paralogous group disruptions and observations presented
from analysis of Lfng and Dll3 mutant animals. The vertebral regions
altered by deletion of individual Hox genes and paralogs are presented
on the left side of the figure (reviewed in Alexander et al., 2009). The presence of multifidus abnormalities observed in Lfng and Dll3 mutants are
presented as a HEAT map, considering axial halves independently for
analysis. Vertebral levels: C, cervical; T, thoracic; L, lumbar.
attach at the craniad insertion point and extend caudally (Deries et al., 2010). This requires large scale patterning cues, which are still largely unknown, that
delimit the cranial and caudal borders of these muscles.
Here we report abnormalities in the cranial and caudal
boundaries of the multifidus muscles in adult mice deficient for either Lfng or Dll3. Although osteological
defects are observed in the ribs and vertebrae of these
mice, alterations in the muscle borders do not simply
map onto these deficits. These findings reveal a
38
FISHER ET AL.
previously unappreciated role of the Notch pathway in
the proper patterning of epaxial muscle groups.
The Notch pathway has been implicated in regulating
the embryonic development of the musculoskeletal system. It functions as a key component of the segmental
clock that controls the periodicity of somite formation
and ultimately the segmental organization of the axial
skeleton (reviewed in Kusumi et al., 2010). Notch1 and
Dll1 have been implicated in the inhibition of muscle
differentiation of myogenic progenitor cells during
embryonic development (Hirsinger et al., 2001; SchusterGosser et al., 2007). Inactivation of Dll1 results in precocious muscle differentiation and hypomorphic fetal
muscles associated with depletion of progenitor cells
(Schuster-Gosser et al., 2007). This is in contrast to the
muscle anomalies observed in the Dll3 and Lfng deficient mice, where the anomalies were restricted to a
small number of muscle groups and led to either the
gain or loss of muscle. This predicts that Notch signaling
can assume multiple roles in myogenesis, as demonstrated by different phenotypes from disruptions of
Notch activation (Dll1 and Notch1) versus mutations in
Notch inhibitors (Dll3 and Lfng).
Specification along the cranial-caudal axis has typically been associated with Hox genes, both in the development of the hindbrain as well as specifying vertebral
identity (reviewed in Alexander et al., 2009). We
observed that mutations in the Notch pathway genes
Dll3 and Lfng led to a cranial shift in the normal multifidus T2 boundary towards C1–C2. In comparing these
findings with Hox mutation phenotypes, single gene
mutations in the Group 4 genes (Hoxa4, Hoxb4, Hoxd4)
produced axial phenotypes in C2–C3 levels while mutations in Group 5 genes (Hoxa5, Hoxb5) produced phenotypes in C6–C7 levels (Fig. 5). Disruption of the entire
Hox paralogous Group 5 set of genes led to axial disruptions ranging from C3 to T2 levels. Thus, the extension
of the cranial multifidus border in Notch mutants corresponds to a region where Hox Group 5 genes play a key
functional role in the paraxial mesoderm. Similarly, the
caudal border of the multifidus is shifted cranially in
Lfng mutant animals, in a zone corresponding to the
lumbar region where Hox paralogous Group 9 plays a
functional role (Fig. 5).
Genetic interactions between the Hox and Notch pathway genes have been investigated. In the paraxial mesoderm, Notch signaling regulates Hoxd1 cyclical
expression (Zákány et al., 2001) leading to changes in
Hox gene expression and vertebral identity (Cordes
et al., 2004). Evidence of converse Hox regulation of
Notch pathway genes has been found in hindbrain rhombomeres, where Hoxb1 activates Notch regulation of
neural stem cells (Gouti and Gavalas, 2008). Further
analysis will be required to determine the mechanism by
which Notch signaling regulates the cranial-caudal borders of epaxial muscles such as multifidus. These investigations may also help elucidate the etiology of
idiopathic scoliosis, as disruptions of the normal development and patterning of these muscles could result in
decreased stability of the vertebral column and
increased lateral flexion and rotation of the spine. Evidence that Notch signaling plays a role in patterning the
multifidus muscle indicates that the genes DLL3 and
LFNG may play a role in the etiology of idiopathic
scoliosis.
ACKNOWLEDGEMENTS
The authors would like to thank Brent Adrian, Brian
Beres, Rajani George, and Allanceson Smith for technical
assistance. We are also grateful to Brent Adrian for producing the illustrations in Fig. 1. The authors would like
to thank Sally Dunwoodie, Randy Johnson, and Susan
Cole for their gift of the Dll3tm1Rbe and Lfngtm1Rjo mouse
mutations, respectively. In addition, we would like to
thank Stephen Pratt for reviewing the manuscript.
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