RET proto-oncogene is important for the development of respiratory CO₂ sensitivity

Abstract

Brain stem muscarinic cholinergic pathways are important in respiratory carbon dioxide (CO₂) chemosensitivity. Defects in the muscarinic system have been reported in children with congenital/developmental disorders of respiratory control such as sudden infant death syndrome (SIDS) and congenital central hypoventilation syndrome (CCHS). This early onset of disease suggests a possible genetic basis. The muscarinic system is part of the autonomic nervous system which develops from the neural crest. Ret proto-oncogene is important for this development. Thus, a potential role for ret in the development of respiratory CO₂ chemosensitivity was considered. Using plethysmography, we assessed the ventilatory response to inhaled CO₂ in the unanesthetized offsprings of ret^+/− mice. Fractional increases in minute ventilation during hypercapnia relative to isocapnia were 5.1±3.2, 3.0±1.6 and 1.4±0.8 for the ret^+/+, ret^+/− and ret^−/− mice, respectively. The ret knockout mice have a depressed ventilatory response to inhaled CO₂. Therefore, the ret gene is an important factor in the pathway of neuronal development which allow respiratory CO₂ chemosensitivity.