Variation of pro-vasopressin processing in parvocellular and magnocellular neurons in the paraventricular nucleus of the hypothalamus: Evidence from the vasopressin-related glycopeptide copeptin.

Natsuko Kawakami,John F Morris,Takumi Oti,Keita Satoh,Keiichi Itoi,Keiko Takanami,Tatsuya Sakamoto,Ashraf H Talukder,Sho Maejima,Yasumasa Ueda,Hirotaka Sakamoto,Akito Otubo

doi:10.1002/cne.25026

Abstract

Arginine vasopressin (AVP) is synthesized in parvocellular- and magnocellular neuroendocrine neurons in the paraventricular nucleus (PVN) of the hypothalamus. Whereas magnocellular AVP neurons project primarily to the posterior pituitary, parvocellular AVP neurons project to the median eminence (ME) and to extrahypothalamic areas. The AVP gene encodes pre-pro-AVP that comprises the signal peptide, AVP, neurophysin (NPII), and a copeptin glycopeptide. In the present study, we used an N-terminal copeptin antiserum to examine copeptin expression in magnocellular and parvocellular neurons in the hypothalamus in the mouse, rat, and macaque monkey. Although magnocellular NPII-expressing neurons exhibited strong N-terminal copeptin immunoreactivity in all three species, a great majority (~90%) of parvocellular neurons that expressed NPII was devoid of copeptin immunoreactivity in the mouse, and in approximately half (~53%) of them in the rat, whereas in monkey hypothalamus, virtually all NPII-immunoreactive parvocellular neurons contained strong copeptin immunoreactivity. Immunoelectron microscopy in the mouse clearly showed copeptin-immunoreactivity co-localized with NPII-immunoreactivity in neurosecretory vesicles in the internal layer of the ME and posterior pituitary, but not in the external layer of the ME. Intracerebroventricular administration of a prohormone convertase inhibitor, hexa-d-arginine amide resulted in a marked reduction of copeptin-immunoreactivity in the NPII-immunoreactive magnocellular PVN neurons in the mouse, suggesting that low protease activity and incomplete processing of pro-AVP could explain the disproportionally low levels of N-terminal copeptin expression in rodent AVP (NPII)-expressing parvocellular neurons. Physiologic and phylogenetic aspects of copeptin expression among neuroendocrine neurons require further exploration.

Highlights

Arginine vasopressin (AVP) is a neuropeptide produced in various hypothalamic nuclei
Across all three species examined in the present study, most N-terminal copeptin expression in rodent AVP (NPII)+ cells exhibited strong copeptin-immunoreactivity in either the supraoptic nucleus (SON), which contains only magnocellular neurons, or the magnocellular part of the paraventricular nucleus (PVN)
Light-microscopic immunoreactivity for NPII and copeptin was observed throughout the intracellular compartment of magnocellular neurons including perikarya, dendrites, and axons

Summary

| INTRODUCTION

Arginine vasopressin (AVP) is a neuropeptide produced in various hypothalamic nuclei. In the PVN, corticotropin-releasing factor (CRF)-producing neurons, located mainly in the anteromedial part of the nucleus, comprise a third population of neuroendocrine neurons that is capable of producing AVP (Fellmann et al, 1984; Itoi et al, 2014;Mouri et al, 1993; Whitnall, 1993) These neurons are parvocellular neurons which project to the external layer of the ME, where CRF and AVP are released into the pituitary portal vessels from nerve endings terminating on the capillary bed (Fellmann et al, 1984). There was a marked species difference in copeptin-immunoreactivity in the parvocellular neurosecretory neurons in the PVN

| MATERIALS AND METHODS

| RESULTS

Findings

| DISCUSSION