Generation of a novel functional neuronal circuit in Hoxa1 mutant mice

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 Ho x family precedes rhombomere formation, and analysis of mouse Hox mutations revealed that they play an important role in the establishment of rhombome re-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 rhombo meric pattern of Hox expression has any influence on the establishment of t he neuronal circuitry of the mature brainstem. The Hoxa1 gene is the earlie st 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 functio nal postnatally. This system develops from mutant rhombomere 3 (r3)-r4 leve ls, includes an ectopic group of progenitors with r2 identity, and integrat es the rhythm-generating network controlling respiration at birth. This is the first demonstration that changes in Hox expression patterns allow the s election of novel neuronal circuits regulating vital adaptive behaviors. Th e implications for the evolution of brainstem neural networks are discussed .