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Development of the Neural Crest–Derived Intrinsic Innervation of the Human Lung

¹ Neural Development Unit, UCL Institute of Child Health, London, United Kingdom

Correspondence and requests for reprints should be addressed to Alan J. Burns, Ph.D., Neural Development Unit, UCL Institute of Child Health, 30 Guilford Street, London WC1N 1EH, UK. E-mail: A.Burns{at}ich.ucl.ac.uk

The formation of neural tissue, in association with airway smooth muscle (ASM), is a feature of normal lung development and function. Intrinsic neuronal tissue has recently been shown, in animal models, to be derived from neural crest cells (NCC). Since defects in NCC development underlie a range of disease states (neurocristopathies), it is important to determine the spatiotemporal development of NCC in the human lung, as defects in their development could have pathophysiologic implications. The aims of this study were to: (1) establish a time course for the formation of ASM and neural tissue within the embryonic and fetal human lung, (2) investigate whether intrinsic neural tissue within the lung is derived from NCC, and (3) gain insight into the possible signaling mechanisms underlying the development of the intrinsic lung innervation. Using human lung tissue from Weeks 6 to 12 of gestation, we analyzed the formation of ASM, NCC, neuronal and glial tissue, and the expression of Gfr1, a receptor component of the RET (rearranged during transfection) tyrosine kinase signaling pathway. Our results showed that NCC accumulated along the branching airways, in close association with the ASM, and differentiated into neurons and glia. Neural crest–derived neural tissue within the lung strongly expressed membrane-bound Gfr1, and soluble Gfr1 was expressed within the lung mesenchyme, but only at early developmental stages. Together these findings indicate that the intrinsic innervation of the human lung is derived from the neural crest.

Key Words: neural crest cells • lung • intrinsic innervation • neurons • RET signaling

CLINICAL RELEVANCE We have shown that the development of intrinsic neural tissue in the human lung is derived from neural crest cells. This could lead to further investigations concerning neural crest–related defects in lung innervation that may be important in lung disease.