1 Laboratoire de Neurologie et Physiologie du Développement, INSERM
EPI9935, Hôpital Robert Debré, 48 Bd Serurier, 75019 Paris,
France
2 CNRS UMR 8542, Département de Biologie, Ecole Normale
Supérieure, 46 rue d'Ulm, 75005 Paris, France
Author for correspondence (e-mail:
jfbrunet{at}biologie.ens.fr)
Accepted 15 September 2003
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SUMMARY |
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Key words: Transcription factor, Autonomic nervous system, Sensory neurons
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Introduction |
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We show that, quite intriguingly, this Phox2b-dependency extends to the three-relay visceral sensory pathway comprising the carotid body, cranial ganglia and the nTS. In the context of our previous work, these new data reveal the developmental requirement for Phox2b throughout the nervous system to be unusually coherent and to correlate neither with neural phenotype, nor spatial coordinates, but connectivity.
Recently, heterozygous mutations in PHOX2B have been found to
correlate with congenital central hypoventilation syndrome (CCHS) or Ondine's
curse, a complex dysautonomic syndrome
(Amiel et al., 2003). The
dependency of visceral afferent pathways on Phox2b that we report
here sheds light on the etiopathology of this disease. In addition, we show
that heterozygous mutants display respiratory anomalies which partially model
the impaired autonomic control of breathing, pathognomonic for CCHS.
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Materials and methods |
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Histology, immunodetection and quantitative analysis
In situ hybridization using lacZ, peripherin, Rnx
(Tlx3 - Mouse Genome Informatics), Tbx20 and Th
antisense riboprobes, immunohistochemistry using Phox2a, Phox2b or Lmx1b
antisera, and combined in situ hybridization with immunohistochemistry were
performed as previously described (Tiveron
et al., 1996). Double-immunofluorescence experiments using Phox2b
and Lmx1b antibodies were analyzed on a Leica microscope. Pictures were
superimposed in Photoshop.
Quantitative analysis of cranial sensory ganglia in Phox2b mutants was carried out by calculating the surface of the ganglia on serial transverse sections stained with peripherin using the QFluoro program (Leica).
Whole-body plethysmography
Breathing variables were measured non-invasively in unanaesthetized,
unrestrained pups using whole-body flow barometric plethysmography
(Dauger et al., 2001).
Frequency and amplitude of respiratory movements, and their product,
ventilation, were calculated from the plethysmographic signal in air (baseline
ventilation), and during hypoxia and hypercapnia. The respiratory tests were
run and analyzed before genotyping 2 days after birth (P2) on 38
Phox2b+/- (weight, 1.52±0.15 g; mouth temperature,
33.7±0.75°C) and 44 Phox2b+/+ pups
(1.57±0.18 g and 33.5±0.58°C); at P6 on 18
Phox2b+/- (2.83±0.23 g and 32.1±0.35°C)
and 13 Phox2b+/+ pups (2.89±0.15 g, and
32.5±0.38°C); and at P10 on 18 Phox2b+/-
(4.96±0.28 g and 32.69±0.25°C) and 21
Phox2b+/+ pups (5.95±0.27 g and
33.5±0.12°C).
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Results |
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Degeneration of epibranchial placode-derived ganglia and of the
carotid body in the absence of Phox2b
Projections to the nTS come from the geniculate, petrosal and nodose
ganglia - the distal ganglia of, respectively, cranial nerves VII, IX and X.
These ganglia develop from epibranchial placodes. Neuronal precursors first
express Phox2a (Tiveron et al.,
1996; Valarché et al.,
1993
) and, in mouse, Ngn2
(Fode et al., 1998
)
[Ngn1 in chick (Begbie et al.,
2002
)], then delaminate and start expressing Phox2b as
they accumulate close to their site of aggregation
(Begbie et al., 2002
;
Fode et al., 1998
;
Pattyn et al., 1997
). We have
previously shown that these ganglia form but become atrophic by midgestation
in both, Phox2a-/- and
Phox2blacZ/lacZ embryos
(Morin et al., 1997
;
Pattyn et al., 1999
). We now
show that, in Phox2blacZ/lacZ embryos, they lose
expression of Phox2a and lacZ (i.e. of the Phox2b
locus) as early as E13.5 (Fig.
2A-F) and continue to degenerate until virtual disappearance by
E16.5 (Fig. 2G-I). The atrophy
of the petrosal-nodose complex, visualized by peripherin expression, was
estimated at 93% by surface area measurements
(Fig. 2I) and, on most
sections, the ganglion appeared fragmented (not shown). The atrophy was thus
more complete than in Phox2a mutants where it was estimated at 77% with the
ganglion retaining histological cohesion at birth
(Morin et al., 1997
). This
denegeration is unlikely to be secondary to the absence of the nTS, as
ganglionic neurons of Rnx mutants survive up to birth even in the
absence of their normal central target
(Qian et al., 2001
).
Therefore, Phox2b expression is absolutely required for the
differentiation and survival of most, and possibly all, epibranchial
placode-derived ganglionic cells.
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A haploinsufficient respiratory phenotype in Phox2b
mutants
From a physiopathological standpoint, our finding that Phox2b
controls the ontogeny of afferent visceral pathways is directly relevant to
the recent report that heterozygous mutations in human PHOX2B are
frequently associated with CCHS syndrome
(Amiel et al., 2003). The
defining dysfunction of CCHS is in the autonomic control of breathing
resulting in hypoventilation, most severe during the non-rapid eye movements
phase of sleep (Gozal, 1998
).
The proposed mechanism of CCHS is an impairment of central integration of
chemoreceptor input (Spengler et al.,
2001
). Furthermore, post-mortem examinations have revealed
abnormal carotid bodies in two individuals
(Cutz et al., 1997
). Thus, the
carotid body, the petrosal ganglion that innervates it and the nTS which
integrates chemoreceptive inputs are all candidates for the main site(s) of
dysfunction. The dependency of all three structures on Phox2b in mice
provides the staightforward basis for a cell-autonomous mechanism of
PHOX2B involvement in CCHS. It is unclear, however, to what extent
the PHOX2B mutations implicated in CCHS [polyalanine expansions and
C-terminal frame shifts (Amiel et al.,
2003
)] are functionally equivalent to the mouse mutation, which is
presumably a null (Pattyn et al.,
1999
). To investigate whether some aspects of CCHS are modeled by
heterozygous mutant mice, we studied the respiratory phenotype of freely
moving Phox2blacZ/+ and
Phox2b+/+ pups. We first tested pups at 48 hours after
birth to minimize the possible confounding effects of postnatal development
and recovery processes. [Such recovery of respiratory impairments have been
reported, for example, in heterozygous Mash1+/-
(Dauger et al., 1999
).] We
examined the ventilatory changes caused by hypoxia (5% O2), which
are mainly mediated by afferences from the carotid body glomus cells to the
nTS via the petrosal ganglion. In newborns, the initial increase in
ventilation caused by hypoxia is followed by a strong ventilatory depression
(Bissonnette, 2000
). We found
that hypoxia resulted in a similar increase in ventilation in
Phox2blacZ/+ and Phox2b+/+
pups, but the total duration of post-hypoxic apneas was strikingly longer in
Phox2blacZ/+ than in
Phox2b+/+ pups (Fig.
3A,B). We also examined the ventilatory increase caused by
hypercapnia (8% CO2), which is mediated by
CO2/H+-sensitive cells widely distributed within the
brainstem and also by carotid body glomus cells
(Nattie, 2001
), which
significantly contribute to this increase [40% in dogs
(Rodman et al., 2001
)]. We
found that the ventilatory response to hypercapnia was markedly lower in
Phox2blacZ/+ than in
Phox2b+/+ pups (Fig.
3C,D). It is notable that, in CCHS, a blunted response to
hypercapnia is also the most prominent ventilatory defect
(Spengler et al., 2001
). We
then examined the respiratory phenotype of
Phox2blacZ/+ and Phox2b+/+
pups at P6 and P10. We focused on the ventilatory response to hypercapnia,
which presented the closest similarity between the CCHS and the
Phox2blacZ/+ respiratory phenotypes. These
responses were not distinguishable between Phox2b+/+ and
Phox2blacZ/+ pups at P10
(Fig. 3E), whereas 6-day-old
pups presented an intermediate phenotype between 2-day- and 10-day-old pups
(P<0.024, not shown).
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Discussion |
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Conversely, the role of Phox2b seems largely restricted to the
ontogeny of these pathways. The major class of Phox2b-dependent
neurons, which seem not to fit in, are bm neurons
(Pattyn et al., 2000b).
However, from a phylogenetic perspective, this exception is only apparent.
Although in amniotes, bm neurons have evolved voluntary functions in the
control of head and jaw muscles, their original major function retained in
fish and amphibia is the control of breathing mostly through the innervation
of gill muscles. Phox2b thus appears to be dedicated to the
differentiation of a set of neuronal classes whose sole, yet salient, point in
common is to interconnect to form the reflex circuits of the visceral nervous
system, most notably in its parasympathetic and enteric divisions. Indeed, the
Phox2b-dependence of all those neurons is not paralleled by any
common feature (other than their belonging to visceral reflex circuits), be it
neurotransmitter phenotype, morphology, position or developmental origin
(which ranges from dorsal and ventral neural tube to neural crest and
neurogenic placodes).
After our suggestion of a hodological correlate for Phox2 gene
expression (Tiveron et al.,
1996), Rnx (Qian et
al., 2001
) and Math1
(Bermingham et al., 2001
) have
been proposed to play roles in specifying visceral and proprioceptive
circuits, respectively. However, among the components of visceral reflex
circuits, only the nTS and medullary noradrenergic centres have been shown to
depend on Rnx, which is also required for proper formation of somatic
sensory neurons and their connections
(Qian et al., 2002
).
Math1 is necessary for the development of several of the synaptic
relays that partake in sensory proprioceptive pathways, but its requirement is
limited to the afferent arms of these circuits, the outputs of which are under
different genetic control. Hence, Phox2b stands out, so far, as a
transcriptional regulator, dependence on which defines entire reflex pathways,
including their afferent and efferent components. This unusually exhaustive
correlation suggests that the expression of Phox2b is causal to the
only common property of Phox2b-dependent neurons: their eventual
synaptic connection to other Phox2b-dependent neurons. Remarkably,
the closest structural relative of Phox2b, Drg11, is expressed in
both, primary and secondary somatic sensory neurons
(Saito et al., 1995
) and
required for projection of the former to the latter
(Chen et al., 2001
). However,
in the case of Phox2b, such a role cannot be tested in simple
knockouts, as abrogation of Phox2b function entails an early
differentiation block (Pattyn et al.,
2000a
; Pattyn et al.,
2000b
; Pattyn et al.,
1999
).
How could expression of a same transcription factor by two (or more)
neuronal classes determine their interconnection? As proposed by Lin et al.
(Lin et al., 1998), the same
transcription factor could, in two synaptic partners, regulate the expression
of homophilic molecules, such as cadherins, which are thought to be required
for synaptogenesis. This scenario could underlie some cases of matching
expression of the Ets-class transcription factors PEA3 and ER81 by connected
proprioceptive sensory and motor neurons of the spinal cord observed in chick
(Lin et al., 1998
) [but not in
mouse (Arber et al., 2000
)].
However, unlike PEA3 and ER81, Phox2b is expressed very early, before any
neurite outgrowth. Therefore, no aspect of the axonal navigation of visceral
neurons can be instructive for Phox2b expression - unlike PEA3 expression by
spinal motor and sensory neurons (Haase et
al., 2002
; Patel et al.,
2003
) - and, conversely, axonal navigation itself should be under
the control of Phox2b if Phox2b is to specify connectivity. One hypothesis is
that Phox2b controls the expression in both presynaptic and
postsynaptic partners of the same receptor for a chemotactic signal that
steers the coordinated migration and appropriate positioning of their
processes or cell bodies. In this respect, it is remarkable that the
establishment of connectivity in visceral reflex circuits is often accompanied
by such coordinated movements. For example, the nTS neurons and the dmnX
neurons [the dendrites of which will eventually invade the nTS
(Shapiro and Miselis, 1985
)]
are born at opposite ventral and dorsal poles of the rhombencephalon and
migrate towards each other to form the compact and extensively connected
`dorsal vagal complex' (this study). Another example is provided by the
di-synaptic extrinsic motor innervation of the enteric nervous system, which
is preceded by the roughly simultaneous rostrocaudal invasion of the gut
mesenchyme by enteric neuronal precursors
(Taraviras and Pachnis, 1999
)
and vagal axons (Baetge and Gershon,
1989
). Interestingly, in this case, Phox2b is required
for the navigation of at least one partner, because, in enteric neurons, it
controls the expression of Ret (Pattyn et
al., 1999
), a co-receptor for GDNF that is required for their
migration (Natarajan et al.,
2002
). As Ret is also regulated by Phox2b in at
least two other visceral neuronal types [sympathetic ganglia and cranial
sensory ganglia (Pattyn et al.,
1999
)] and as GDNF-family ligands (GFLs) are also involved in the
migration and/or axonal guidance of other visceral neurons, namely sympathetic
and parasympathetic ganglionic neurons
(Enomoto et al., 2001
;
Enomoto et al., 2000
;
Hashino et al., 2001
;
Honma et al., 2002
), the
Ret/GFL signalling system is an appealing candidate for a mechanistic
underpinning of our model.
Phox2b heterozygous neonates as models of congenital central
hypoventilation syndrome
Recently, the pleiotropic role of Phox2b in the ontogeny of the
visceral nervous system was given a physiopathological dimension as human
PHOX2B was found to be mutated in a majority of cases of a complex
genetic dysautonomia: congenital central hypoventilation syndrome or Ondine's
Curse (Amiel et al., 2003). It
has already been noted by these authors that most of the incompletely
penetrant symptoms of CCHS [such as multiple neuroblastomas, Hirschprung
disease, paralysis of the pupils, cardiac rhythm disturbances or dysphagia
(Croaker et al., 1998
;
Gozal, 1998
)] involve
Phox2b-dependent neuronal classes
(Pattyn et al., 1999
), in
these cases, autonomic ganglionic neurons. The present study provides
mechanistic insight into the main, defining symptom of CCHS (impaired
autonomic control of breathing) by showing that three neuronal types involved
in sensing hypoxia and hypercapnia are strictly dependent on Phox2b
for their differentiation: the carotid body, the petrosal chemoreceptors that
innervate it and the nTS on which they project
(Finley and Katz, 1992
).
Moreover, our study demonstrates that partial loss of function of
Phox2b (by heterozygoty) leads to dysfunction of the respiratory
system, which partly model the respiratory phenotype of CCHS and to dysgenesis
of petrosal chemoreceptors, which may underlie this neonatal respiratory
phenotype. Our data do not preclude additional haploinsufficient defects in
CO2/H+-sensitive cells located in the carotid body, the
nTS or the locus coeruleus (Nattie,
2001
), which all depend on Phox2b (this study)
(Pattyn et al., 2000a
).
The recovery of the ventilatory response to hypercapnia in elder mutant
pups confirms the considerable postnatal plasticity of respiratory control
(Feldman et al., 2003). It was
paralleled by a normalization of the number of Th+ neurons
in the petrosal ganglion - most probably owing to the de novo expression of
Th in Phox2+ neurons
(Brosenitsch and Katz, 2002
) -
consistent with a causative role of these cells in the transient respiratory
anomalies of heterozygous mutants. However, it is possible that
Phox2b-dependent respiratory inputs are superceded by
CO2/H+-sensitive sites that do not express
Phox2b and are therefore spared by its mutation [e.g. the midline
raphé, the hypothalamus and the fastigial nucleus of the cerebellum
(Feldman et al., 2003
)].
Determining whether this recovery, not observed in individuals with CCHS,
reflects a difference in the control of breathing between humans and mice, or
in the severity of the Phox2b mutation will await future studies. The
polyalanine extension and C-terminal frame shift mutation found in CCHS
(Amiel et al., 2003
) could lead
to hypomorphic or dominant negative alleles or even cellular toxicity in the
case of polyalanine extensions, which may not be modeled by the mouse
mutation. However, as frame-shift mutations cause a clinically
indistinguishable syndrome, a dose-related effect, resulting from
haploinsufficiency or dominant-negative action, seems most likely.
It should be noted that Phox2b expression persists at postnatal
stages in several neural structures, such as the carotid body
(Brosenitsch and Katz, 2002) or
the nTS (Pattyn et al., 1997
).
Therefore, it is conceivable that, apart from developmental defects such as
the one we report in petrosal chemoreceptors, the respiratory disorder of CCHS
could also reflect the disruption of post-developmental roles of
Phox2b.
Finally, this study raises the possibility that Phox2b could be
involved in cases of sudden infant death syndrome, in which anomalies in the
catecholamine content of carotid bodies have been found
(Perrin et al., 1984). More
generally, given the richness and variability of the clinical picture of CCHS,
it is tempting to speculate that mutations in this gene could underlie yet
other congenital autonomic dysfunctions or dysplasia.
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ACKNOWLEDGMENTS |
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Footnotes |
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