Identification and characterization of a new neural brain-to-bone pathway regulating bone mass accrual

Abstract

In the last decade, the hypothalamus has appeared as a potent regulator in the central nervous system controlling anabolic pathways of bone remodelling. Our work in zebrafish has revealed a new neuropeptide produced by a specific subset of neurones exclusively located in the lateral hypothalamus, which appears as a novel parathyroid hormone family member unique to non-eutherian vertebrates. Expression analysis by whole mount in situ hybridization allowed us to trace the development of PTH-L positive cells from onset of expression at 22 h post-fertilization through the first week of development in zebrafish. Promoter bashing experiments using enhanced green fluorescent protein allowed us to identify the minimal promoter region able to accurately mimic the native PTH-L pattern during zebrafish development and the specific regulatory elements. This enhanced green fluorescent protein expression also revealed a complex pattern of projections within the hypothalamus, to the midbrain, and to the spinal cord. Functional studies using a stable PTH-L transgenic zebrafish line have revealed the PTH-L as powerful regulator of bone mass accrual. Our results, therefore, define a new neural brain-to-bone pathway involving efferent neural signal from hypothalamus to receptors on bone cells controlling skeletal development This work was partly funded by PhDs grants (FPI BES-2009-016797) and (PhD Campus Do Mar-Xunta de Galicia Scholarship) to TNE and SBP, respectively, by BFU2010-14875 and 2009SGR336 to CC, and by the MICIN AGL2008-00392/ACU and AGL2011-23581 grant projects.