The extensive reorganization in rhombomeres 3 and 5 of the Egr-2 null mice eliminates most RTN neurons ( Thoby-Brisson et al., 2009), but neurons outside of Egr-2 domain may compensate for the lethality caused by loss of RTN neurons. In our case, we propose that some of the RL-derived Atoh1 neurons could function collectively as a second excitatory source for the preBötC, which might stochastically reach the excitatory threshold

to allow survival of half the newborn Atoh1Phox2bCKO mice. Although the paratrigeminal neurons are anatomically intact without Atoh1, their role in respiratory control remains unknown, and we do not exclude the possibility that they modulate find more breathing in an Atoh1-dependent Onalespib ic50 manner. RL-independent and dependent Atoh1-positive neuronal subpopulations might each contribute to neonatal respiratory activity to

a similar extent. Fifty percent of newborn mice with Atoh1 deletion in the Wnt-1 lineages, which affect most of the RL-derived neurons, die within 24–36 hr of birth ( Morrison et al., 2009), which lends further support to this hypothesis. Loss of Atoh1 causes aberrant RTN neuronal migration, analogous to the consequence of loss of atonal during the development of the Drosophila dorsal cluster (DC) neurons. Atonal is expressed in the postmitotic DC neurons that innervate the optic lobes ( Hassan et al., 2000); in its absence, the DC neurons are still present, but are aberrantly positioned and show severely impaired target innervation and loss of axonal arborization. Atonal thus does not act as a classical proneural gene in the DC Astemizole neurons. Interestingly, the ability of atonal/Atoh1 to control cell positioning and target innervation is limited to the few populations where these bHLH factors are expressed postmitotically. The identity of central chemoreceptors and the mechanism by which they detect elevated pCO2 and stimulate breathing remain unclear, but

these questions are currently under intense investigation (Guyenet, 2012). The Atoh1Phox2bCKO surviving mice provide an unexpected opportunity to assess the extent to which mislocalized RTN neurons affect adult chemoresponsiveness. We observed that the Atoh1Phox2bCKO surviving mice develop a significantly impaired hypercapnic response and hypersensitivity to hypoxia, suggesting that despite the possible development of compensatory mechanisms, the Atoh1-mediated development of the RTN neurons remains a crucial step that assures proper chemosensory response throughout life. During embryonic stage, the fictive motor activity of Atoh1Phox2bCKO embryos is significantly slower than WT embryos under both baseline and pH challenge; but unlike the CCHS mouse models that lose the RTN and express Phox2b27Ala in multiple brain regions ( Dubreuil et al., 2008; Ramanantsoa et al., 2011), the pH response is virtually unchanged in the Atoh1Phox2bCKO embryos.