CFTR-deficient pigs display peripheral nervous system defects at birth

Abstract

Peripheral nervous system abnormalities, including neuropathy, have been reported in people with cystic fibrosis. These abnormalities have largely been attributed to secondary manifestations of the disease. We tested the hypothesis that disruption of the cystic fibrosis transmembrane conductance regulator (CFTR) gene directly influences nervous system function by studying newborn CFTR −/− pigs. We discovered CFTR expression and activity in Schwann cells, and loss of CFTR caused ultrastructural myelin sheath abnormalities similar to those in known neuropathies. Consistent with neuropathic changes, we found increased transcripts for myelin protein zero, a gene that, when mutated, can cause axonal and/or demyelinating neuropathy. In addition, axon density was reduced and conduction velocities of the trigeminal and sciatic nerves were decreased. Moreover, in vivo auditory brainstem evoked potentials revealed delayed conduction of the vestibulocochlear nerve. Our data suggest that loss of CFTR directly alters Schwann cell function and that some nervous system defects in people with cystic fibrosis are likely primary.

Cystic Fibrosis and the Nervous System

“…Interestingly, in humans with CF, the number of pulmonary neuroendocrine cells is elevated. 73,74 Our studies in the pig suggest that innervation of the sinuses 55 and trachea 75 is also decreased. …”

“…37 In pigs, CFTR is expressed in both the peripheral and central nervous systems. 55,56 In humans, CFTR has been identified in parvocellular ganglion, 57 hypothalamic neurons, 58 spinal cord neurons, 59 ganglion cells of the heart, 60 and sympathetic ganglion. 61 Both neuronal and glial cell CFTR expression has been reported in multiple species, 55,[62][63][64] with the exception of humans, in whom only neuronal CFTR has been reported.…”

Air Trapping and Airflow Obstruction in Newborn Cystic Fibrosis Piglets

“…Pulmonary innervation begins very early in gestation (47) and baseline airway caliber is in part regulated by neural control (49). Innervation abnormalities have been reported in the airways of a CF mouse model (50), and we recently reported that pigs with CF have nervous system abnormalities at birth (51). Might altered nervous system function and/or innervation contribute to the airway phenotype?…”

Cystic Fibrosis Transmembrane Conductance Regulator Protein (CFTR) Expression in the Developing Human Brain

“…In autopsy reports of adults with CF, axonal dystrophy has been described in 75% of the brains as well as in the few examined spinal cords (Cavalier and Gambetti 1981;Cochran et al 1991). Even if these symptoms may result from a complex association of diabetes, autoimmunity and vitamin deficiency, a primary CFTR defect is also likely to be involved as shown by the recent report of peripheral nervous system defects observed in CFTR -/-pigs at birth (Reznikov et al 2013). Concerning CFTR protein function, recent works have studied CFTR activity in motor neurons of the spinal cord or brainstem nuclei in rats during neonatal development (Ostroumov et al 2007;Morales et al 2011) and have shown that CFTR contributes to the relatively depolarized equilibrium potential for synaptic inhibition, an important process to control hyperexcitability and seizure-predisposition in neonates (Ostroumov et al 2007).…”