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The Journal of Neuroscience, August 1, 2001, 21(15):5637-5642
Generation of a Novel Functional Neuronal Circuit in
Hoxa1 Mutant Mice
Eduardo Domínguez
del
Toro1,
Véronique
Borday1,
Marc
Davenne2,
Rüdiger
Neun2,
Filippo M.
Rijli2, and
Jean
Champagnat1
1 Neurobiologie Génétique et
Intégrative, Unité Propre de Recherche 2216, Centre
National de la Recherche Scientifique (CNRS), 91198 Gif-sur-Yvette,
France, and 2 Institut de Génétique et de
Biologie Moléculaire et Cellulaire, CNRS/Institut National de la
Santé et de la Recherche Médicale/Université Louis
Pasteur, Collège de France, BP 163-67404 Illkirch,
Centre Universitaire de Strasbourg, France
Early organization of the vertebrate brainstem is characterized by
cellular segmentation into compartments, the rhombomeres, which follow
a metameric pattern of neuronal development. Expression of the homeobox
genes of the Hox family precedes rhombomere formation, and analysis of mouse Hox mutations revealed that they
play an important role in the establishment of
rhombomere-specific neuronal patterns. However, segmentation is a
transient feature, and a dramatic reconfiguration of neurons and
synapses takes place during fetal and postnatal stages. Thus, it is not
clear whether the early rhombomeric pattern of Hox
expression has any influence on the establishment of the neuronal
circuitry of the mature brainstem. The Hoxa1 gene is the
earliest Hox gene expressed in the developing hindbrain.
Moreover, it is rapidly downregulated. Previous analysis of mouse
Hoxa1 / mutants has focused on
early alterations of hindbrain segmentation and patterning. Here, we
show that ectopic neuronal groups in the hindbrain of
Hoxa1/ mice establish a
supernumerary neuronal circuit that escapes apoptosis and becomes
functional postnatally. This system develops from mutant rhombomere 3 (r3)-r4 levels, includes an ectopic group of progenitors with r2
identity, and integrates the rhythm-generating network controlling
respiration at birth. This is the first demonstration that changes in
Hox expression patterns allow the selection of novel
neuronal circuits regulating vital adaptive behaviors. The implications
for the evolution of brainstem neural networks are discussed.
Key words:
homeobox genes; Hoxa1 knock-out; respiration; suction; rhythm generation; rhombomeres; neural progenitors; migratory pathways; neuronal networks, reticular formation; pons; hindbrain; brainstem; newborn mice
Copyright © 2001 Society for Neuroscience 0270-6474/01/21155637-06$05.00/0
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