Download Transgenic Models to Study Disorders of Respiratory Control in

Transgenic Models to Study Disorders of Respiratory Control in Newborn Mice
Claude Gaultier, Boris Matrot, and Jorge Gallego
Abstract
Recent studies described the in vivo respiratory phenotype
of mutant newborn mice with targeted deletions of genes
involved in respiratory control development. Whole-body
flow barometric plethysmography is the noninvasive
method of choice for studying unrestrained newborn mice.
The main characteristics of the early postnatal development
of respiratory control in mice are reviewed, including available data on breathing patterns and on hypoxic and hypercapnic ventilatory responses. Mice are very immature at
birth, and their instable breathing is similar to that of preterm infants. Breathing pattern abnormalities with prolonged apneas occur in newborn mice that lack genes
involved in the development of rhythmogenesis. Some mutant newborn mice have blunted hypoxic and hypercapnic
ventilatory responses whereas others exhibit impairments in
responses to hypoxia or hypercapnia. Furthermore, combined studies in mutant newborn mice and in humans have
helped to provide pathogenic information on genetically determined developmental disorders of respiratory control in
humans.
Key Words: chemosensitivity; congenital central hypoventilation syndrome; genetics; human newborns; hypercapnia;
hypoxia; newborn mice; plethysmography
Investigating the Respiratory Control
Phenotype in Newborn Mice
Introduction
G
enetic research into respiratory control is finding
new paths for investigating developmental respiratory control disorders in humans, such as apneas of
prematurity, sudden infant death syndrome, and congenital
central hypoventilation syndrome (CCHS1) (Gaultier et al.
Claude Gaultier, M.D., Ph.D., Boris Matrot, Eng., and Jorge Gallego,
Ph.D., are Professor of Physiology, Project Manager, and Researcher, respectively, in the Service de Physiologie and Inserm U676, Hôpital Robert
Debré, Paris, France.
1
Abbreviations used in this article: CCHS, congenital central hypoventilation syndrome; Ece1, endothelin-converting enzyme 1; Edn1, endothelin 1;
Ednra, endothelin receptor a; HVD, hypoxic ventilatory decline; preBötzC,
pre-Bötzinger complex; Bdnf, brain-derived neurotrophic factor; Mash-1,
mammalian achaete-scute homologous 1 gene; PACAP, pituitary adenylcyclase-activating polypeptide; Ret, rearranged-during-transfection gene;
Phox2b, paired-like homeobox 2b gene.
Volume 47, Number 1
2004). Studies in newborn mice with targeted gene deletions have started to establish links among the expressions
of specific genes involved in the development of individual
respiratory-control components, such as rhythmogenesis
and chemosensitivity for oxygen and carbon dioxide. Furthermore, combined studies in mutant newborn mice and in
humans have helped to provide pathogenic information on
genetically determined disorders of respiratory control development in humans. Pulmonary gas exchange provides
oxygen to developing cells in all mammalian species (with
the exception of skin breathing in some species [Mortola et
al. 1999]). Respiratory control impairments at early stages
of development compromise brain oxygenation and are
thought to account for irreversible motor and cognitive
disorders.
This review focuses on in vivo studies of respiratory
phenotype in mutant newborn mice. First, methods for testing respiratory control are described briefly. Second, the
main characteristics of the early postnatal development of
respiratory control in mice are reviewed. In mice, the developmental stage at birth roughly matches that of human
preterm neonates born at 25 wk of gestational age (Marret et
al. 1995). Finally, the respiratory phenotype of mutant newborn mice with targeted deletion of genes involved in the
development of respiratory control is detailed.
2006
Breathing is usually quantified based on breath duration,
inspiratory and expiratory duration, tidal volume, and ventilation. These variables are measured not only while the
animals breathe air but also during exposure to hypercapnia,
hypoxia, or hyperoxia to test for chemosensitivity. In addition, the number and duration of apneas and periodic breathing episodes are indicators of respiratory instability, a
characteristic of the neonatal period in newborn mammals.
Analyzing the respiratory phenotype of mutant mice at
birth is of crucial importance for two main reasons. First,
null mutants for most genes of interest die within a few
hours after birth, possibly from respiratory failure, which
leaves very little time to investigate respiratory function.
Second, breathing control is the outcome of numerous adaptation processes, including plasticity and learning. These
processes may lead to resolution of respiratory impairment
present early after birth, thereby masking the effects of a
gene mutation (Dauger et al. 1999b, 2003).
15
The small birth weight (1.3 g) and tidal volume (3-4
␮L/g) in newborn mice preclude the use of measurement
devices that are widely accepted for adult mice or larger
animals (e.g., pneumotachometers, thermistors, respiratory
inductance spirometers, magnetometers). Two methods provide valid measurements in newborn mice: head-out plethysmography (e.g., Burton et al. 1997) and whole-body
plethysmograpy (e.g., Dauger et al. 1999a,b, 2003).
In head-out plethysmography, the newborn mouse is
placed in a chamber and its head is slipped outside the
chamber through an opening with an airtight seal around the
neck. The amount of air that moves in and out of the chamber as a result of breathing is roughly proportional to the
changes in chest volume. This method provides a relatively
direct measurement of breathing. Its main drawback is that
the animal must be tightly restrained to ensure that no air
leakage occurs around the neck. As a rule, restraint is a
potent stressor that has marked effects on the baseline
breathing pattern in adult mice (Dauger et al. 1998). Although the effects have not been studied in newborn mice,
stress probably exerts a major influence on ventilatory data
collected using head-out plethysmography.
Whole-body flow barometric plethysmography consists of placing the animal in a chamber and measuring the
pressure changes inside the box. The pressure in the chamber increases during inspiration because of the addition of
water vapor to the inspired gas and because of the warming
of the inspired gas from the temperature in the chamber to
that in the alveoli. Conversely, pressure diminishes during
expiration because of condensation of water vapor and cooling of expired gas. This method provides an indirect semiquantitative measure of breathing variables. It has been
validated against pneumotachography in adult mice (Onodera et al. 1997) but not in newborns. In newborn mice,
whole-body plethysmography provides semiquantitative
measurements of tidal volume and ventilation while allowing valid measurement of breathing frequency and apnea. It
is important to control for body temperature, which can
influence the results, most notably when stimuli may affect
metabolism (typically hypoxia or hyperoxia). The zone of
thermoneutrality is known for rat pups (Blumberg and Sokoloff 1998) but not for mice pups. However, it may be
assumed that the temperature inside the litter (32-33°C) is
appropriate for respiratory measurements. Furthermore, this
limitation does not preclude genotype group comparisons,
which form the basis of phenotype studies. The flow bias
through the plethysmograph allows continuous measurement without CO2 accumulation over long periods, which is
crucial when studying the time-course of ventilatory responses, delayed effects (e.g., posthypoxic period after
switching back to normoxia), repeated stimulations, and effects of behavioral states (Durand et al. 2004). At present,
whole-body flow barometric plethysmography is the only
noninvasive method and is therefore the method of choice
for studying unrestrained newborn mice.
Apneas, sighs, and gasps can be identified by visual
examination of the plethysmographic signal. However, au16
tomatic detection methods based on spectral analysis for
apnea detection facilitate phenotyping of large numbers of
mutant animals (Matrot et al. 2005). Behavioral states
(wakefulness, active sleep, quiet sleep, or undetermined
sleep) were determined recently using nuchal muscle tone,
coordinated limb movements, and motor twitches in newborn mice (Durand et al. 2005). It is not possible to determine sleep states by electroencephalogram or electrooculogram in newborn rodents (Karlsson and Blumberg
2002).
Maturation of Respiratory Control and
Arousal Responses to Chemical Stimuli in
Newborn Mice
Rapid changes occur postnatally in baseline breathing pattern and ventilatory responses to hypercapnia and hypoxia
in newborn mice (Renolleau et al. 2001a). Newborn mice
show an extremely immature pattern of breathing reminiscent of the respiratory instability in human preterm infants.
At birth, breathing is characterized by numerous apneas,
which disappear gradually as age increases (Matrot et al.
2005).
The ventilatory response to hypoxia increases sharply
after birth due to peripheral chemoreceptor resetting in newborn mammals (Gaultier and Gallego 2005). This resetting
occurs approximately 2 to 12 hr after birth in newborn mice
(Renolleau et al. 2001a). The time-course of the hypoxic
ventilatory responses in wild-type newborn mice during the
first 24 hr after birth is reported in Figure 1. During sustained hypoxia, newborn mammals exhibit a biphasic ventilatory response with an initial hyperpneic phase followed
by a decline in ventilation to below the normoxic level
(hypoxic ventilatory decline [HVD1]) (Gaultier and Gallego
2005). Furthermore, ventilation remains decreased and apneas may occur during the posthypoxic period after switching back to normoxia in some newborn mice (Figure 2). The
ventilatory response to hypercapnia is present and vigorous
at birth (Renolleau et al. 2001a) and then increases steadily
until adulthood (Robinson et al. 2000).
Behavioral arousal has been defined as a stereotyped
motor response characterized by sudden neck and forepaw
extension. At 48 hr of postnatal age, this stereotyped pattern
of motor activity is followed by head-raising (Durand et al.
2004). Arousal from sleep in response to hypoxia is a critical defense reflex that is triggered by afferent messages
from mechanoreceptors and/or oxygen-sensitive chemoreceptors. Few studies have addressed the development of the
hypoxic arousal response during the early postnatal period.
In mice, arousal has been shown to occur during the hypoxic
decline in all age groups, indicating that mechanoreceptor
input was not sufficient to trigger arousal (Dauger et al.
2001). Arousal may therefore contribute to the hypoxic ventilatory response in the early postnatal period in mice, and it
thus deserves consideration in studies of respiratory control
maturation in newborns. In particular, abnormal developILAR Journal
Figure 1 Hypoxic ventilatory response from 1 hr (H1) to 24 hr
(H24) after birth in wild-type newborn mice. Newborn mice were
exposed to 10% O2, 3% CO2, and 87% N2 during 4 min within a
whole-body flow barometric plethysmograph. The hypoxic ventilatory response (VE) is expressed as a percentage of the baseline
VE in normoxia-normocapnia. The time-course of the hypoxic
ventilatory response shows an initial increase in VE (hyperpneic
ventilatory response [HVR]) followed by a decrease in VE (hypoxic ventilatory decline [HVD]). At H1, the hypoxic HVR is weak,
and VE falls below the baseline level during the HVD. At H12 and
H24, the HVR is stronger than at H1, whereas the HVD is less
marked. The data suggest that resetting of the peripheral chemoreceptors may occur around H6-H12. Values are group means ±
s.e.m. Reprinted with permission from Renolleau S, Dauger S,
Autret F, Vardon G, Gaultier C, Gallego J. 2001a. Maturation of
baseline breathing and of hypercapnic and hypoxic ventilatory
resonses in newborn mice. Am J Physiol Integr Comp Physiol
281:R1746-R1753.
ment of the central mechanisms of arousal may account for
the impaired responsiveness to hypoxia observed in some
newborn mutant mice (Renolleau et al. 2001b). Furthermore, studies of arousal latency are helpful for examining
habituation to a chemical stimulus. Experiments in newborn
mice have shown that intermittent hypoxia rapidly and reversibly lengthens arousal latency from baseline levels increased after the first hypoxic stimulus, thereby delaying
arousal in newborn mice (Durand et al. 2004).
Respiratory Phenotype in Mutant
Newborn Mice
Survival differs across mutant newborn mice. Examples of
homozygous mutant mice that have died in utero include
paired-like homeobox 2b (Phox2b 1 ) and endothelinconverting enzyme 1 (Ece11) mouse embryos (Pattyn et al.
1999; Yanagisawa et al. 1998). Among mutant mice born
Volume 47, Number 1
2006
alive, many die within a few hours. In general, heterozygous
mutant newborn mice develop normally, which allows for
longitudinal testing. However, irrespective of the targeted
gene deletion, surviving mutant newborn mice usually
weigh less than wild-type pups and require normalization of
ventilation for body weight. Genotype-related differences in
breathing variables can be further examined in weightmatched groups of mutant and wild-type pups. Yet one or
more respiratory control abnormalities may occur in mutant
newborn mice, which complicates the interpretation of deficiencies in each individual component of respiratory control. Finally, the problem of appropriate genetic controls for
comparison with genetically modified newborn mice is an
important issue. The phenotypic effects of a mutation probably depend on the genetic background, as demonstrated in
other settings (Nadeau 2001). The modifier genes responsible for this respiratory phenotype variability could perhaps
be identified by interstrain comparisons. To date, no such
experiment has been reported in newborn mutant mice.
Mutant Newborn Mice with Abnormal
Baseline Breathing
Studies of breathing rhythmicity in mutant newborn mice
have yielded new information about the genes that control
rhythmogenesis. Pioneer studies demonstrated that loss of
genes responsible for hindbrain segmentation during the
early embryonic stages, such as Krox20, led to severe
breathing instability at birth that usually resulted in death
(Borday et al. 2004). However, studies have shown that
neurotrophic factors, such as the brain-derived neurotrophic
factor (Bdnf1), play a pivotal role in respiratory rhythm
development in mice (Erickson et al. 1996). Bdnf nullmutant newborn mice exhibit severe disruption of respiratory rhythmogenesis, with bradypnea and numerous apneas
(Erickson et al 1996). Recording of brainstem-spinal cord
preparations from Bdnf newborn mutant mice have shown
discharge frequency attenuation, which has been more
marked in homozygous than in heterozygous newborns
(Erickson et al. 2001). Bdnf appears critical to respiratory
rhythmogenesis in neonatal mice through the Bdnf receptor
tyrosine kinase B in neurons of the pre-Bötzinger complex
(preBötzC1) (Thoby-Brisson et al. 2003). The preBötzC
complex is thought to underlie rhythmogenesis (Feldman et
al. 2003).
Another group of studies has focused on the role of
respiratory drive modulation by the A5 and A6 noradrenergic nuclei in mutant newborn mice lacking one of the
genes that control noradrenergic neuronal development (Hilaire et al. 2004). Loss of the inhibitory influence of A5
(Errchidi et al. 1991) leads to abnormally fast breathing, as
observed in null-mutant newborn mice lacking the mammalian achaete-scute homologous 1 gene (Mash-11) (Dauger et
al. 1999a), the respiratory neuron homeobox gene Rnx (Shirasawa et al. 2000), or the glial cell line-derived neuro17
Figure 2 Examples of breathing pattern in normoxia, hypoxia, and posthypoxic normoxia in a heterozygous Ret mutant newborn (c-ret +/-)
(top) and a wild-type newborn (c-ret+/+) (bottom). The traces during hypoxia corresponded to the hyperpneic phase of the hypoxic response.
The traces during posthypoxic normoxia were selected 2 min after switching back to air. In both pups, breathing was depressed and irregular
during posthypoxic normoxia, but only the Ret +/- pup exhibited apneas and periodic breathing. Reprinted with the permission of Elsevier
from Aizenfisz S, Dauger S, Durand E, Vardon G, Levacher B, Simonneau M, Gaultier C, Gallego J. 2002. Ventilatory responses to
hypercapnia and hypoxia in heterozygous c-ret +/- newborn mice. Respir Physiol 131:213-222.
trophic factor gene (Gdnf1) (Huang et al. 2005); all these
mutant mice die shortly after birth. Recent evidence suggests that the A6 pontine noradrenergic center may be essential for normal respiratory rhythmogenesis in neonatal
mice (Viemari et al. 2004). Phox2a null-mutant neonatal
mice, which lack A6 neurons, exhibit numerous apneas and
gasps and die shortly after birth.
Recent studies have shed light on the genes involved in
preBötzC development. Deficiency of the transcription factor MafB causes defective respiratory rhythmogenesis in
neonatal mutant mice, which manifests as gasps and fatal
apneas shortly after birth (Blanchi et al. 2003). The human
orthologue of the Necdin gene is mutated in patients with
Prader-Willi syndrome, which is characterized by abnormal
respiratory control, and null-mutant mice for Necdin exhibit
respiratory rhythm instability, which is fatal within a few
hours after birth (Ren et al. 2003). Medullary slice preparations from the preBötzC regions of these null-mutant embryos on embryonic day 18.5 show abnormal rhythmic
discharges that suggest loss or alteration of the function of
preBötzC rhythmic neurons (Ren et al. 2003). Finally, newborn mice that lack the transcription factor Nurr1, which
governs the development of midbrain dopaminergic neurons, exhibit disturbed breathing patterns with numerous
apneas and die shortly after birth (Nsegbe et al. 2004).
Mutant Newborn Mice with Abnormal
Chemosensitivity (Table 1)
Abnormal Ventilatory Response to Hypoxia
and Hypercapnia
Abnormal ventilatory responses to both sustained hypoxia
and sustained hypercapnia have been reported in mutant
newborn mice lacking endothelin pathway genes that
encode endothelin (Edn11) and the endothelin receptor a
18
(Ednra1) (Kuwaki et al. 1999). These mutant newborn mice
die shortly after birth (Kuwaki et al. 1999). In contrast, the
ventilatory responses to hypoxia and hypercapnia are normal in mutant mice that lack genes for the endothelin 3
signaling pathway (Kuwaki et al. 1999). Recent evidence
shows that null-mutant newborn mice deficient in pituitary
adenylcyclase-activating polypeptide (PACAP1), a member
of the vasoactive intestinal peptide superfamily, have
blunted ventilatory responses to both hypoxia and hypercapnia. This evidence suggests that the PACAP signaling
pathway may contribute to both hypoxic and hypercapnic
chemosensitivity (Cummings et al. 2003).
Abnormal Ventilatory Response to Hypoxia or
to Hyperoxia
Other gene disruptions alter only the hypoxic ventilatory
response in mutant newborn mice. Heterozygous mutant
newborn mice lacking Ece1 survive after birth and exhibit
an abnormal hyperpneic ventilatory response to hypoxia
that persists during adulthood (Renolleau et al. 2001b).
Nurr1 null-mutant newborn mice have deficient ventilatory
responses to hypoxia and die shortly after birth (Nsegbe et
al. 2004). Because Nurr1 is expressed in the nucleus tractus
solitarius, which is the first central relay of the arterial chemoreflex, loss of function of this gene may explain the
deficient ventilatory response to hypoxia in mutant mice.
Hyperpneic ventilatory responses to hypoxia at birth are
not affected by heterozygous disruption of genes involved
in the development of the autonomic nervous system, such
as the rearranged-during-transfection gene (Ret1) or Phox2b
(Aizenfisz et al. 2002; Dauger et al. 2003). However, the
HVD is exaggerated in these mutant newborn mice. Conversely, the HVD is attenuated by disruption of other genes;
thus, the HVD is weak in null-mutant mice lacking the
beta-2 subunit of the nicotinic acetylcholine receptors
ILAR Journal
Table 1 Ventilatory responses to hypoxia and hypercapnia in knock-out newborn micea
Hypoxic
Newborn
mice
Age at
study
Hypercapnic
VR␣
Ret−/−
Ret+/−
Mash+/−
Phox2b+/−
Edn1−/−
Ednra−/−
Ecel+/−
Nurr−/−
Bdnf−/−
PACA−/−
Beta−
2nAChR−/−
A few hours
12 hr
⬙⬙
48 hr
First day
First day
A few hours
First day
First 4 days
Day 4
48 hr
Decreased*a
NSa
Decreased †a
Decreased
Decreased
Decreased
NS
NS
Present
Decreased
HVRa
NS
NS
NS
NS
Decreased
Decreased
Decreased
Decreased
HVDa
Hyperoxic
VR
Increased
Increased
Absent
Decreased
NS
Decreased
References
(see text)
Burton et al. 1997
Aizenfisz et al. 2002
Dauger et al. 1999a,b
Dauger et al. 2003
Kuwaki et al. 1999
Kuwaki et al. 1999
Renolleau et al. 2001
Nsegbe et al. 2004
Erickson et al. 1996
Cummings et al. 2004
Dauger et al. 2004
a
VR, ventilatory response; HVR, hyperpneic ventilatory response; HVD, hypoxic ventilatory decline; beta-2nAChR, beta-2 subunit of the nicotinic
acetylcholine receptors; NS, not significantly different from wild-type littermates; *, significantly decreased compared with wild-type littermates;
†, significantly decreased in males; for other abbreviations, see text.
(Dauger et al. 2004). These findings suggest alterations in
the inhibitory processes that affect the ventilatory response
to hypoxia in neonates. Ventilatory responses to hyperoxia,
which reflect peripheral chemoreceptor function, are absent
in Bdnf null-mutant newborn mice (Table 1) (Erickson et al.
1996), presumably due to loss of chemoafferent neurons
(Erickson et al. 2001).
Phox2b mutant mice (Dauger et al. 2003) and is no longer
present in adult Mash-1 mice (Dauger et al. 1999b). Compensatory mechanisms and/or plasticity processes may explain the recovery of ventilatory responses to hypercapnia in
these mutant mice, although the underlying mechanisms
remain unexplored.
Conclusion and Perspectives
Abnormal Ventilatory Response
to Hypercapnia
Abnormal ventilatory responses to hypercapnia have been
reported in newborn mice that lack genes of the Mash-1Ret-Phox2b pathway, which is involved in the development
of the autonomic nervous system. Null-mutant newborn
mice lacking the Ret gene, but not mice heterozygous for
this mutation, have blunted ventilatory responses to hypercapnia (Aizenfisz et al. 2002; Burton et al. 1997). Male
heterozygous Mash-1 mutant newborn mice show decreased
ventilatory responses to hypercapnia (Dauger et al. 1999b).
Finally, heterozygous mutant mice that lack the Phox2b
gene, whose human orthologue is mutated in CCHS patients
(Amiel et al. 2003; Trochet et al. 2005), exhibit a reduced
ventilatory response to hypercapnia on postnatal day 2 (Figure 3). Furthermore, these mutants have sleep apneas (Durand et al. 2005). Ret, Mash-1, and Phox2b are expressed in
central chemosensitive areas, such as the nucleus tractus
solitarius and the locus coeruleus in newborn mice (Dauger
et al. 1999a, 2003). Loss of expression of these factors may
explain the deficient ventilatory response to hypercapnia in
mutant mice. Interestingly, the deficiency in ventilatory responses to hypercapnia resolves on postnatal day 10 in
Volume 47, Number 1
2006
Studies of the respiratory phenotype of mutant newborn
mice have been helpful in understanding how gene disruption may disturb one or several components of respiratory
control during postnatal development. Although many
genes involved in respiratory control have been identified,
none of the genetically engineered mice developed to date
fully replicate the phenotype of human disorders in respiratory control development. However, studies of the respiratory phenotype of mutant newborn mice combined with
studies in humans have provided valuable pathogenic information on genetically determined disorders of respiratory
control development in humans (e.g., congenital central hypoventilation syndrome and Prader-Willi syndrome). It is
thus clearly important to extend these studies to early disturbances of respiratory control, including apneas of prematurity and sudden infant death syndrome.
In vivo studies of the respiratory phenotype should be
combined with in vitro studies of brainstem-spinal cord
preparations and/or brain slices in culture to describe in full
the consequences of gene disruption in isolated neurons,
isolated brainstem, and live animals. Furthermore, technological improvements should allow integrative approaches
that encompass not only respiration but also all vital func19
Figure 3 Hypercapnic ventilatory responses in heterozygous newborn mice lacking Phox2b and in wild-type pups on postnatal day 2.
Newborn mice were exposed to 8% CO2, 21% O2, and 71% N2 during 3 min within a whole-body flow barometric plethysmograph. Panel
a: Ventilatory tracings of one Phox2b +/+ pup (top) and one Phox2b +/- pup (bottom); both pups had similar baseline ventilation, but the
Phox2b+/- pup exhibited a weaker ventilatory response to hypercapnia. Panel b: The ventilatory increase during hypercapnia in Phox2b+/pups was approximately half that in Phox2b+/+ pups, because of a smaller increase in breathing frequency. Values are group means ± s.e.m.
Reprinted with permission from Dauger S, Pattyn A, Lofaso F, Gaultier C, Goridis C, Gallego J, Brunet JF. 2003. Phox2b controls the
development of peripheral chemoreceptors and afferent visceral pathways. Development 130:6635-6642.
tions of mutant newborn mice. Recordings of respiratory
variables should be combined with recordings of heart rate,
temperature, and behavioral states (Durand et al. 2005).
Research into the respiratory phenotype of newborn mice is
an important component of current international efforts to
determine the function of genes and their role in human
diseases and to design new treatment strategies. Neonatal
phenotyping is mandatory for exploring the molecular
mechanisms of early disturbances in respiratory control,
which are not faithfully reflected by the adult phenotype,
and their impact on neurodevelopment.
References
Aizenfisz S, Dauger S, Durand E, Vardon G, Levacher B, Simonneau M,
Gaultier C, Gallego J. 2002. Ventilatory responses to hypercapnia and
hypoxia in heterozygous c-ret +/- newborn mice. Respir Physiol 131:
213-222.
Amiel J, Laudier B, Attie-Bitach T, Trang H, De Pontual L, Gener B,
Trochet D, Etchevers H, Ray P, Simonneau M, Vekemans M, Munnich
20
A, Gaultier C, Lyonnet S. 2003. Polyalanine expansion and frameshift
mutations of the paired-like homeobox gene PHOX2B in congenital
central hypoventilation syndrome. Nat Genet 33:459-461.
Blanchi B, Kelly LM, Viemari JC, Lafon I, Burnet H, Bevengut M,
Tillmans S, Daniel L, Graf T, Hilaire G, Sieweke MH. 2003. MafB
deficiency causes defective respiratory rhythmogenesis and fatal central apnea at birth. Nat Neurosci 6:1091-1100.
Blumberg MS, Sokoloff G. 1998. Thermoregulatory competence and behavioural expression in young of altricial species-revisited. Dev Psychobiol 33:107-123.
Borday C, Wrobe, L, Fortin G, Champagnat J, Thaëron-Antôno C, ThobyBrisson M. 2004. Developmental gene control of brainstem function:
Views from the embryo. Prog Biophys Mol Biol 84:89-106.
Burton MD, Kawashima A, Brayer JA, Kazemi H, Shannon DC, Schuchardt A, Costantini F, Pachnis V, Kinane TB. 1997. RET protooncogene is important for the development of respiratory CO2 sensitivity. J Autonom Nerv Syst 63:137-143.
Cummings KJ, Pendlebury JD, Sherwood NM, Wilson RJA. 2003. Sudden
neonatal death in PACAP-deficient mice is associated with reduced
respiratory chemoresponse and susceptibility to apnoea. J Physiol 555:
15-26.
Dauger S, Aizenfisz S, Renolleau S, Durand E, Vardon G, Gaultier C,
Gallego J. 2001. Arousal response to hypoxia in newborn mice. Respir
Physiol 128:235-240.
ILAR Journal
Dauger S, Durand E, Cohen G, Lagercrantz H, Changeux JP, Gaultier C,
Gallego J. 2004. Control of breathing in newborn mice lacking the
beta-2nAChR subunit. Acta Physiol Scand 181:1-8.
Dauger S, Guimiot F, Renolleau S, Levacher B, Boda B, Mas C, Nepote V,
Simonneau M, Gaultier C, Gallego J. 1999a. Mash-1/Ret pathway involvement in development of brain stem control of respiratory frequency in newborn mice. Physiol Genomics 7:49-157.
Dauger S, Nsegbe E, Vardon G, Gaultier C, Gallego J. 1998. The effects
of restraint on ventilatory responses to hypercapnia and hypoxia in
adult mice. Respir Physiol 112:215-252.
Dauger S, Pattyn A, Lofaso F, Gaultier C, Goridis C, Gallego J, Brunet JF.
2003. Phox2b controls the development of peripheral chemoreceptors
and afferent visceral pathways. Development 130:6635-6642.
Dauger S, Renolleau S, Nepote V, Mas C, Simonneau M, Gaultier C,
Gallego J. 1999b. Ventilatory responses to hypercapnia and to hypoxia
in Mash-1 heterozygous newborn and adult mice. Pediatr Res 46:535542.
Durand E, Dauger S, Pattyn A, Gaultier C, Goridis C, Gallego J. 2005.
Sleep-disordered breathing in newborn mice heterozygous for the transcription factor Phox2b. Am J Respir Crit Care Med: Apr 28 (Epub
ahead of print).
Durand E, Lofaso F, Dauger S, Vardon G, Gaultier C, Gallego J. 2004.
Intermittent hypoxia induces transient arousal delay in newborn mice.
J Appl Physiol 96:1216-1222.
Erickson JT, Conover JC, Borday V, Champagnat J, Barbacid M, Yancopoulos G, Katz DM. 1996. Mice lacking brain-derived neurotrophic
factor exhibit visceral sensory neuron losses distinct from mice lacking
NT4 and display a severe developmental deficit in control of breathing.
J Neurosci 16:5361-5371.
Erickson JT, Brosenitsch TA, Katz DM. 2001. Brain-derived neurotrophic
factor and glial cell line-derived neurotrophic factor are required simultaneously for survival of dopaminergic primary sensory neurons in
vivo. J Neurosci 15:581-589.
Errchidi S, Monteau R, Hilaire G. 1991. Noradrenergic modulation of the
medullary respiratory rhythm generator in the newborn rat: An in vitro
study. J Physiol 443:477-498.
Feldman JL, Mitchell GS, Nattie EE. 2003 Breathing: Rhythmicity, plasticity, chemosensitivity. Annu Rev Neurosci 26:239-266.
Gaultier C, Amiel J, Dauger S, Trang H, Lyonnet S, Gallego J, Simonneau
M. 2004. Genetics and early disturbances of breathing control. Pediatr
Res 55:729-733.
Gaultier C, Gallego J. 2005. Development of respiratory control: Evolving
concepts and perspectives. Respir Physiol Neurobiol June 4, 2005
(Epub ahead of print).
Hilaire G, Viemari JC, Coulon P, Simonneau M, Bévengut M. 2004.
Modulation of the respiratory rhythm generator by the pontine noradrenergic A5 and A6 groups in rodents. Respir Physiol Neurobiol 143:
187-197.
Huang L, Guo H, Hellard DT, Katz DM. 2005. Glial cell line-derived
neurotrophic factor (GDNF) is required for differentiation of pontine
noradrenergic neurons and patterning of central respiratory output.
Neuroscience 130:95-105.
Karlsson KA, Blumberg MS. 2002. The union of the state: Myoclonic
twitching is coupled with nuchal atonia in infants rats. Behav Neurosci
116:912-917.
Kuwaki T, Ling GY, Onodera M, Ishii T, Nakamura A, Ju KH, Cao Wh,
Kumada M., Kurihara H, Kurihara Y, Yazaki Y, Ohuchi T, Yanagisawa M, Fukuda Y. 1999. Endothelin in the central control of cardio-
Volume 47, Number 1
2006
vascular and respiratory functions. Clin Exp Pharmacol Physiol 26:
989-994.
Marret S, Mukendi R, Gadisseux JF, Gressens P, Evrard P. 1995. Effect of
ibotenate on brain development: An excitotoxic mouse model of microgyria and posthypoxic-like lesions. J Neuropathol Exp Neurol 54:
358-370.
Matrot B, Durand E, Dauger S, Vardon, Gaultier, Gallego J. 2005. Automatic classification of activity and apneas using whole-body plethysmography in newborn mice. J Appl Physiol 98:365-370.
Mortola JP, Frappell PB, Woolley PA. 1999. Breathing through skin in a
newborn mammal. Nature 397:660.
Nadeau JH. 2001. Modifiers genes in mice and humans. Nat Rev 2:165174.
Nsegbe E, Wallen-Mackensie A, Dauger S, Roux JC, Shvarev Y, Lagercrantz H, Perlman T, Herlenius E. 2004. Congenital hypoventilation
hypoxic response in Nurr1 mutant mice. J Physiol 556:43-59.
Onodera M, Kuwaki T, Kumada M, Masuda Y. 1997. Determination of
ventilatory volume in mice by whole body plethysmography. Jpn J
Physiol 47:317-326.
Pattyn A, Morin X, Cremer H, Goridis C, Brunet JF. 1999. The homeobox
gene Phox2b is essential for the development of autonomic neural crest
derivatives. Nature 399:366-370.
Ren J, Lee S, Pagliardini S, Gerard M, Stewart CL, Greer JJ, Wevrick R.
2003. Absence of Ndn, encoding the Prader-Willi syndrome-deleted
gene necdin, results in congenital deficiency of central respiratory drive
in neonatal mice. J Neurosci 23:1569-1573.
Renolleau S, Dauger S, Autret F, Vardon G, Gaultier C, Gallego J. 2001a.
Maturation of baseline breathing and of hypercapnic and hypoxic ventilatory responses in newborn mice. Am J Physiol Integr Comp Physiol
281:R1746-R1753.
Renolleau S, Dauger S, Vardon G, Levacher B, Simonneau M, Yanagisawa
M, Gaultier C, Gallego J. 2001b. Impaired ventilatory responses to
hypoxia in mice deficient in endothelin-converting-enzyme-1. Pediatr
Res 49:705-712.
Robinson DM, Kwork H, Adams BM, Peebles KC, Funk GD. 2000. Development of the ventilatory response to hypoxia in Swiss CD-1 mice
J Appl Physiol 88:1907-1914.
Shirasawa S, Arata A, Onimaru H, Roth KA, Brown GA, Horning S, Arata
S, Okumura K, Sasazuki T, Korsmeyer SJ. 2000. Rnx deficiency results
in congenital hypoventilation. Nat Genet 24:287-290.
Thoby-Brisson M, Cauli B, Champagnat J, Fortin G, Katz DM. 2003.
Expression of functional tyrosine kinase B receptors by rhythmically
active respiratory neurons in the pre-Bötzinger complex of neonatal
mice. J Neurosci 23:7685-7689.
Trochet D, O’Brien LM, Gozal D, Nordenskjold A, Laudier B, Svensson
PJ, Uhrig S, Cole T, Munnich A, Gaultier C, Lyonnet S, Amiel J. 2005.
PHOX2B genotype allows for prediction of tumour risk in congenital
central hypoventilation syndrome. Am J Hum Genet 76:421-426.
Viemari JC, Bevengut M, Burnet H, Coulon P, Pequignot JM, Tiveron MC,
Hilaire G. 2004. Phox2a gene, A6 neurons, and noradrenaline are essential for development of normal respiratory rhythm in mice. J Neurosci 24:928-937.
Yanagisawa H, Yanakisawa M, Kapur RP, Richardson JA, Williams SC,
Clouthier DE, de Wit D, Emoto N, Hammer RE. 1998. Dual genetic
pathway of endothelin-mediated intracellular signaling revealed by targeted disruption of endothelin converting enzyme-1 gene. Development 125:825-836.
21