Generation of a novel functional neuronal circuit in Hoxa1 mutant mice.
Résumé
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.
Mots clés
Mutant Strains
Morphogenesis
Nerve Net cytology
Neurons cytology
drug effects
Periodicity
Phenotype
Pons cytology embryology
Respiratory Center
Rhombencephalon
Transcription Factors
biosynthesis
deficiency
genetics
alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid
Homeobox genes
Hoxa1 knock-out
respiration
suction
rhythm generation
rhombomeres
neural progenitors
migratory pathways
neuronal networks
reticular formation
hindbrain
brainstem
newborn mice
Apoptosis
Biological Clocks
Brain Stem
Excitatory Amino Acid Agonists
In Vitro
Domaines
Neurosciences [q-bio.NC]
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