45 ± 9.86 min−1), VT (10.10 ± 0.45 μl ⋅ g−1), and VE (2.97 ± 0.19 ml ⋅ min−1 ⋅ g−1) ( Figure 6A). The compromised hypercapnic response might be due to the inability of the RTN neurons to detect changes in pCO2 and trigger respiration owing to their failed migration. At the same time, the

partially preserved hypercapnic response implies that the carotid bodies are spared. To test if the carotid bodies are functionally intact, we challenged Atoh1Phox2bCKO mice (n = 9) and their littermates (WT, n = 21) with hypoxic gas http://www.selleckchem.com/products/gsk1120212-jtp-74057.html (10% O2). Interestingly, Atoh1Phox2bCKO mice displayed a stronger hypoxia-evoked ventilatory response than WT (RF: 346.63 ± 14.36 versus 286.53 ± 4.75 min−1; VT: 12.8 ± 0.74 versus 11.05 ± 0.34 μl ⋅ g−1; VE: 4.5 ± 0.33 versus 3.11 ± 0.11 ml ⋅ min−1 ⋅ g−1) ( Figure 6B), suggesting that the O2-sensing carotid bodies could provide compensatory feedback. Overall, our results demonstrate that transient Atoh1 expression in postmitotic RTN neurons is critical for mediating respiratory Proteasome inhibitor chemoresponsiveness in free-moving adult mice,

most likely through promoting their ventral localization. This study has yielded three important findings. First, Atoh1 expression in the RTN neurons is critical for neonatal survival. Second, expression of Atoh1 in the postmitotic RTN neurons directs their migration through the embryonic hindbrain and establishes the connectivity that provides excitatory drive crucial for commencing

inspiratory rhythm at birth. This cell-autonomous role for Atoh1 in RTN migration provides a mechanism by which derailed hindbrain development can result in disordered neonatal breathing and highlights the importance of the RTN neurons at this stage. Third, Atoh1-mediated RTN development at an early embryonic stage is necessary for normal respiratory chemosensitivity in the adult. Genetic removal of Atoh1 from the Phox2b neurons results in nearly 50% neonatal lethality and indicates that even transient Atoh1 embryonic expression plays a major role in neonatal respiration. Given that the glutamatergic RTN neurons have been hypothesized whatever to entrain the embryonic preBötC ( Bochorishvili et al., 2012; Thoby-Brisson et al., 2009), we proposed that the migration defect of the Atoh1Phox2bCKO mice and the consequent loss of synaptic contact dramatically decreases excitatory input, thereby challenging the neonatal respiratory rhythm-generating network ( Feldman et al., 2003; Mellen et al., 2003). Support for this contention comes from the ability of Atoh1Phox2bCKO en bloc preparations to still generate respiratory rhythm (albeit depressed), which confirms the participation of RTN neurons in neonatal respiratory rhythm modulation. Once the conditional mutants survive past P0, they do not show additional lethality, similar to the partially penetrant neonatal lethality of the Egr-2 null mice (∼50% at P0) ( Jacquin et al., 1996).