Prolactin and teleost ionocytes: new insights into cellular and molecular targets of prolactin in vertebrate epithelia

Abstract

The peptide hormone prolactin is a functionally versatile hormone produced by the vertebrate pituitary. Comparative studies over the last six decades have revealed that a conserved function for prolactin across vertebrates is the regulation of ion and water transport in a variety of tissues including those responsible for whole-organism ion homeostasis. In teleost fishes, prolactin was identified as the "freshwater-adapting hormone", promoting ion-conserving and water-secreting processes by acting on the gill, kidney, gut and urinary bladder. In mammals, prolactin is known to regulate renal, intestinal, mammary and amniotic epithelia, with dysfunction linked to hypogonadism, infertility, and metabolic disorders. Until recently, our understanding of the cellular mechanisms of prolactin action in fishes has been hampered by a paucity of molecular tools to define and study ionocytes, specialized cells that control active ion transport across branchial and epidermal epithelia. Here we review work in teleost models indicating that prolactin regulates ion balance through action on ion transporters, tight-junction proteins, and water channels in ionocytes, and discuss recent advances in our understanding of ionocyte function in the genetically and embryonically accessible zebrafish (Danio rerio). Given the high degree of evolutionary conservation in endocrine and osmoregulatory systems, these studies in teleost models are contributing novel mechanistic insight into how prolactin participates in the development, function, and dysfunction of osmoregulatory systems across the vertebrate lineage.

Keywords: Differentiation; Gill; NCC; Osmoregulation; Pituitary; Zebrafish.

Figure 1. Models for Prolactin (PRL) Regulation of Ionocytes.

(A-D) 72 hour post fertilization (hpf) zebrafish embryos labeled to reveal ncc-expressing ionocytes in the epidermis. (A,C) In control embryos, approximately 300 ionocytes in the epidermis express ncc by 72 hpf. Ionocytes are concentrated over the yolk sac and epidermis of the head, including the developing branchial arches (arrow head). Scale bar = 200 μm. Panel C shows a higher magnification view of ncc-expressing ionocytes dispersed in the skin posterior to the eye. Scale bar = 40 μm. (B,D) Morpholino (MO) knockdown of prl function results in a diminished number of ncc-expressing ionocytes in the epidermis, while ecac- and nhe3b-expressing ionocytes are unaffected (data not shown). Panel D shows a higher magnification view and the approximately 70% reduction in ncc-expressing cells. Ionocyte Progenitor Model for Prolactin Action. (E) In zebrafish embryos, epidermal stem cells (SCs) expressing p63 and foxi1 give rise to skin keratinocytes and foxi3a-expressing ionocyte progenitors. These progenitors subsequently differentiate into ionocytes (NaR-cells, HR-cells or NCC-cells). Prolactin may act on ionocyte progenitors to drive differentiation of ncc-expressing ionocytes (NCC-cells), or to increase proliferation of NCC precursor cells. In this diagram, signaling initiated by the binding of prolactin to one of the two prolactin receptors activates JAK/STAT, Ras/Raf/MAPK, Src kinases, or PI3K second messengers, activating genes that drive NCC-cell differentiation. ncc Transcription Model for Prolactin Action. (F) Alternatively (or in addition), prolactin could act directly and specifically on differentiated NCC-cells to modulate expression from the ncc locus. Ionocyte lineage diagram adapted from Hwang and Chou (2013).