Generation of a Novel Functional Neuronal Circuit in<i>Hoxa1</i>Mutant Mice

Toro, Eduardo Domı́nguez del; Borday, Véronique; Davenne, Marc; Neun, Rüdiger; Rijli, Filippo M.; Champagnat, Jean

doi:10.1523/jneurosci.21-15-05637.2001

Cited by 75 publications

(47 citation statements)

References 31 publications

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“…Breathing defects that result from abnormal development of brainstem respiratory circuits have previously been described in genetically altered mice. In several mutants such as Mash1 (Dauger et al, 2004), Phox2a (Morin et al, 1997;Viemari et al, 2004), Phox2b (Pattyn et al, 2000a), Rnx (Shirasawa et al, 2000), Hoxa1 (del Toro et al, 2001), Krox20 (Jacquin et al, 1996), Ret (Viemari et al, 2005), and MafB (Blanchi et al, 2003), life-threatening apneas or irregularities of the respiratory rhythm have been demonstrated, but so far, none has shown a complete extinction of respiratory activity. These mutants preserve the capacity to generate inspiratory bursts even if their occurrence may be considerably reduced in frequency (Blanchi et al, 2003).…”

Section: Vglut2mentioning

confidence: 99%

Vesicular Glutamate Transporter 2 Is Required for Central Respiratory Rhythm Generation But Not for Locomotor Central Pattern Generation

Gezelius²,

et al. 2006

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Glutamatergic excitatory neurotransmission is dependent on glutamate release from presynaptic vesicles loaded by three members of the solute carrier family, Slc17a6 -8, which function as vesicular glutamate transporters (VGLUTs). Here, we show that VGLUT2 (Slc17a6) is required for life ex utero. Vglut2 null mutant mice die immediately after birth because of the absence of respiratory behavior. Investigations at embryonic stages revealed that neural circuits in the location of the pre-Bötzinger (PBC) inspiratory rhythm generator failed to become active. However, neurons with bursting pacemaker properties and anatomical integrity of the PBC area were preserved. Vesicles at asymmetric synapses were fewer and malformed in the Vglut2 null mutant hindbrain, probably causing the complete disruption of AMPA/kainate receptor-mediated synaptic activity in mutant PBC cells. The functional deficit results from an inability of PBC neurons to achieve synchronous activation. In contrast to respiratory rhythm generation, the locomotor central pattern generator of Vglut2 null mutant mice displayed normal rhythmic and coordinated activity, suggesting differences in their operating principles. Hence, the present study identifies VGLUT2-mediated signaling as an obligatory component of the developing respiratory rhythm generator.

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Section: Vglut2mentioning

confidence: 99%

Vesicular Glutamate Transporter 2 Is Required for Central Respiratory Rhythm Generation But Not for Locomotor Central Pattern Generation

Gezelius²,

et al. 2006

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“…Although the Hoxa1 mutation does not affect lung development per se, it results in perinatal death caused by anoxia, a problem due to defective hindbrain patterning. 21 The combined mutation of the Hoxa1 and Hoxb1 genes results in hypoplastic lungs with a reduced number of lobes but a normal histology, implying some functional redundancy between Hox1 paralogs during lung formation. 22 The Hoxa3 gene participates to the patterning of the proximal airways, more specifically to the development of the larynx.…”

Section: Hoxa5mentioning

confidence: 99%

Impact of the Loss of Hoxa5 Function on Lung Alveogenesis

Mandeville

Aubin

LeBlanc

et al. 2006

The American Journal of Pathology

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The involvement of genes controlling embryonic processes in the etiology of diseases often escapes attention because of the focus given to their inherent developmental role. Hoxa5 belongs to the Hox gene family encoding transcription factors known for their role in skeletal patterning. Hoxa5 is required for embryonic respiratory tract morphogenesis. We now show that the loss of Hoxa5 function has severe repercussions on postnatal lung development. Hoxa5؊/؊ lungs present an emphysema-like morphology because of impaired alveogenesis. Chronic inflammation characteristics, including goblet cell hyperplasia, mucus hypersecretion, and recruitment of inflammatory cells, were also observed. Altered cell specification during lung morphogenesis triggered goblet cell anomalies. In addition, the defective motility of alveolar myofibroblast precursors in the embryonic lung led to the mispositioning of the alveolar myofibroblasts and to abnormal elastin deposition postnatally. Both goblet cell hyperplasia and elastic fiber abnormalities contributed to the chronic physiopathological features of Hoxa5 ؊/؊ lungs. They constituted an attractive stimulus to recruit activated macrophages that in turn generated a positive feedback loop that perpetuated macrophage accumulation in the lung. The present work corroborates the notion that altered Hox gene expression may predispose to lung pathologies. Lung morphogenesis relies on finely orchestrated processes that initiate from the outpocketing and the elongation of the foregut endoderm into the surrounding mesenchyme. The lung bud then branches extensively giving rise to saccules that expend and subdivide to ultimately produce alveoli. In the mouse, the main stem bronchi form at approximately embryonic day (E) 9.5, and ramification organized by signaling centers shapes the respiratory tree during the pseudoglandular period that extends from E14.0 to E16.5. At late gestational stages, saccules are found at the end of each terminus of the pulmonary tree. The last step of lung morphogenesis occurs between postnatal day (P) 5 and P30, and it aims at multiplying the respiratory surface for vital gas exchanges after birth by modifying the distal lung architecture through the process of alveogenesis. During each step of lung development, the concerted action of transcriptional regulators, signaling molecules, their associated receptors and downstream effectors governs branching morphogenesis and lung maturation by integrating cellular proliferation, differentiation, apoptosis, and migration.

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“…Hoxb1 expression in r4 persists until E13 and modulates neurogenesis in this segment. In the Hoxa1 mutant mouse, expression of Hoxb1 and other downstream genes are altered, the brainstem respiratory circuits are malformed, and Hoxa1 newborn mutants die of apnea (del Toro et al 2001;Tvrdik and Capecchi 2006). The Hoxb1 mutant, on the other hand, is viable but displays facial paralysis due to the absence of the seventh cranial nerve originating from rhombomere 4 (Goddard et al 1996).…”

mentioning

confidence: 99%

Fitness Assays Reveal Incomplete Functional Redundancy of the HoxA1 and HoxB1 Paralogs of Mice

et al. 2015

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Gene targeting techniques have led to the phenotypic characterization of numerous genes; however, many genes show minimal to no phenotypic consequences when disrupted, despite many having highly conserved sequences. The standard explanation for these findings is functional redundancy. A competing hypothesis is that these genes have important ecological functions in natural environments that are not needed under laboratory settings. Here we discriminate between these hypotheses by competing mice (Mus musculus) whose Hoxb1 gene has been replaced by Hoxa1, its highly conserved paralog, against matched wildtype controls in seminatural enclosures. This Hoxb1 A1 swap was reported as a genetic manipulation resulting in no discernible embryonic or physiological phenotype under standard laboratory tests. We observed a transient decline in first litter size for Hoxb1 A1 homozygous mice in breeding cages, but their fitness was consistently and more dramatically reduced when competing against controls within seminatural populations. Specifically, males homozygous for the Hoxb1 A1 swap acquired 10.6% fewer territories and the frequency of the Hoxb1 A1 allele decreased from 0.500 in population founders to 0.419 in their offspring. The decrease in Hoxb1 A1 frequency corresponded with a deficiency of both Hoxb1 A1 homozygous and heterozygous offspring. These data suggest that Hoxb1 and Hoxa1 are more phenotypically divergent than previously reported and support that sub-and/or neofunctionalization has occurred in these paralogous genes leading to a divergence of gene function and incomplete redundancy. Furthermore, this study highlights the importance of obtaining fitness measures of mutants in ecologically relevant conditions to better understand gene function and evolution.KEYWORDS fitness assay; functional redundancy; Hoxa1; Hoxb1; intraspecific competition; subfunctionalization G ENE targeting techniques have led to the phenotypic characterization of thousands of genes across eukaryotes (for reviews see Thorneycroft et al. 2001;Capecchi 2005;Collins et al. 2007) and this characterization continues as this invaluable technology develops (e.g., Meyer et al. 2012;Hsu et al. 2014). However, an estimated 10-15% of mouse genes show minimal to no phenotypic consequences when disrupted (mouse appears normal), despite many having highly conserved sequences (Barbaric et al. 2007). One explanation for these findings is functional redundancy-genes throughout the genome, typically paralogs of disrupted genes, code for the same, or at least overlapping, functions (Nowak et al. 1997;Kafri et al. 2009). A competing explanation for "no phenotype" gene disruptions is that these genes have important ecological functions in natural environments that are not needed, or are of minimal importance, within laboratory settings. Here we discriminate between these hypotheses by using mice that have experienced a manipulation previously reported to have no embryonic or physiological phenotype, wherein the coding sequence of the Hoxb1 gene has ...

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Generation of a Novel Functional Neuronal Circuit inHoxa1Mutant Mice

Cited by 75 publications

References 31 publications

Vesicular Glutamate Transporter 2 Is Required for Central Respiratory Rhythm Generation But Not for Locomotor Central Pattern Generation

Vesicular Glutamate Transporter 2 Is Required for Central Respiratory Rhythm Generation But Not for Locomotor Central Pattern Generation

Impact of the Loss of Hoxa5 Function on Lung Alveogenesis

Fitness Assays Reveal Incomplete Functional Redundancy of the HoxA1 and HoxB1 Paralogs of Mice

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