Early Development of Hypothalamic Neurons Expressing Proopiomelanocortin Peptides, Neuropeptide Y and Kisspeptin in Fetal Rhesus Macaques

Abstract

We have documented the early embryonic development of hypothalamic neurons expressing β-endorphin (β-End), α-melanocyte stimulating hormone (αMSH), neuropeptide Y (NPY) and kisspeptin (Kiss1) in Rhesus macaques, an animal model that is very similar to humans. Neurons expressing both β-End and αMSH are the first to develop and are initially located in the lateral basal hypothalamus (LBH) as early as day 32-34 of gestation. By day 45 of gestation, these neurons have migrated into the medial basal hypothalamic (MBH) area as their final destination. NPY neurons within the ARH develop later and are first documented at day 44 of fetal life, at which time a cluster of neurons are present within ARH-MBH area. NPY neurons continued to be expressed within the ARH area at all later fetal ages analyzed. Similarly, kisspeptin neurons develop later compared to β-End, although, only a few cells are present in the ARH by day 44 of gestation, at which time kisspeptin is also expressed in the developing anterior lobe of the pituitary. By day 70 of gestation, the rostral to caudal distribution and cell size of Kiss1 neurons within the MBH was found to be similar in females and males. In addition, Kiss1 fibers were also expressed in the POA by day 70. By day 130 of gestation, Kiss1 neurons exhibited a wider dorsal and lateral distribution within the MBH, with highly increased fiber distribution. Therefore, the development of these neurons is much earlier than what had been described previously for αMSH and NPY in primates.

Significance Statement The arcuate nucleus of the hypothalamus express β-End/αMSH, NPY and kisspeptin neurons, which together are essential for feeding, metabolism, puberty and fertility. The early development of these neurons in Rhesus macaques, which have a long gestation period similar to humans, is not known. Here we show that these neurons start developing within the hypothalamus between day 32 and 44 of gestation and are almost fully developed by mid gestation in Rhesus macaques. Given that maternal high fat diet during pregnancy in primates has been shown to affect melanocortin expression and metabolic health in the mother’s offspring, it would be important to know the birthdate and in utero development of these critical neurons in order to prevent postnatal health deficiencies.