Distinct roles of Hoxa2 and Krox20 in the development of rhythmic neural networks controlling inspiratory depth, respiratory frequency, and jaw opening.
BACKGROUND
Little is known about the involvement of molecular determinants of segmental patterning of rhombomeres (r) in the development of rhythmic neural networks in the mouse hindbrain. Here, we compare the phenotypes of mice carrying targeted inactivations of Hoxa2, the only Hox gene expressed up to r2, and of Krox20, expressed in r3 and r5. We investigated the impact of such mutations on the neural circuits controlling jaw opening and breathing in newborn mice, compatible with Hoxa2-dependent trigeminal defects and direct regulation of Hoxa2 by Krox20 in r3.


RESULTS
We found that Hoxa2 mutants displayed an impaired oro-buccal reflex, similarly to Krox20 mutants. In contrast, while Krox20 is required for the development of the rhythm-promoting parafacial respiratory group (pFRG) modulating respiratory frequency, Hoxa2 inactivation did not affect neonatal breathing frequency. Instead, we found that Hoxa2-/- but not Krox20-/- mutation leads to the elimination of a transient control of the inspiratory amplitude normally occurring during the first hours following birth. Tracing of r2-specific progenies of Hoxa2 expressing cells indicated that the control of inspiratory activity resides in rostral pontine areas and required an intact r2-derived territory.


CONCLUSIONS
Thus, inspiratory shaping and respiratory frequency are under the control of distinct Hox-dependent segmental cues in the mammalian brain. Moreover, these data point to the importance of rhombomere-specific genetic control in the development of modular neural networks in the mammalian hindbrain.
Chatonnet
Fabrice
F
NGI, UPR 2216, Institut de Neurobiologie Alfred Fessard IFR2218, Centre National de Recherche Scientifique, F-91198 Gif sur Yvette Cedex, France. Fabrice.Chatonnet@ens-lyon.org
Wrobel
Ludovic J
LJ
Mézières
Valérie
V
Pasqualetti
Massimo
M
Ducret
Sébastien
S
Taillebourg
Emmanuel
E
Charnay
Patrick
P
Rijli
Filippo M
FM
Champagnat
Jean
J
D000818:Animals; D000831:Animals, Newborn; D019521:Body Patterning / Q000235:genetics; D051767:Early Growth Response Protein 2 / Q000235:genetics* / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental / Q000235:genetics; D018398:Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism; D007568:Jaw / Q000294:innervation / Q000502:physiology*; D008410:Masticatory Muscles / Q000254:growth & development / Q000294:innervation; D051379:Mice; D018345:Mice, Knockout; D009415:Nerve Net / Q000254:growth & development* / Q000378:metabolism; D010507:Periodicity; D012125:Respiratory Center / Q000254:growth & development* / Q000378:metabolism; D012143:Respiratory Physiological Phenomena; D012249:Rhombencephalon / Q000254:growth & development* / Q000378:metabolism; D014276:Trigeminal Nerve / Q000254:growth & development / Q000378:metabolism
D051767:Early Growth Response Protein 2; C497327:Egr2 protein, mouse; D018398:Homeodomain Proteins; C489833:Hoxa2 protein, mouse