Prolactin from Pluripotency to Central Nervous System Development

Omar Martinez-Alarcon, Guadalupe García-Lopez, Jose Raul Guerra Mora, Anayansi Molina-Hernandez, Nestor Emmanuel Diaz-Martinez, Wendy Portillo, Nestor Fabian Diaz
2021 Neuroendocrinology  
Prolactin (PRL) is a versatile hormone that exerts more than 300 functions in vertebrates, mainly associated with physiological effects in adult animals. Although the process that regulates early development is poorly understood, evidence suggests a role of PRL in the early embryonic development regarding pluripotency and nervous system development. Thus, PRL could be a crucial regulator in oocyte preimplantation and maturation as well as during diapause, a reversible state of blastocyst
more » ... ment arrest that shares metabolic, transcriptomic and proteomic similarities with pluripotent stem cells in the naïve state. Thus, we analyzed the role of the hormone during those processes, which involve the regulation of its receptor and several signaling cascades (Jak/Mapk, Jak/Stat, PI3k/Akt), resulting in either a plethora of physiological actions or their dysregulation, a factor in developmental disorders. Finally, we propose models to improve the knowledge on PRL function during early development. Early mammalian development is a complex phenotypic process involving cells that interact with environmental signals that provide instructions such as cellular differentiation, migration, positioning, and maturation. Thus, full-organized organism development begins at the fecundation of a viable egg that progresses to a blastocyst able to produce all body cell types. This capability comprises the pluripotency property. Later, the embryo goes through a post-implantation process with a strictly spatial and temporal regulation. However, the precise role of crucial molecules directing these processes is not elucidated. Multiple extracellular signals, such as hormones, have a relevant function during ontogenesis, i.e., growth hormone and placental lactogen. Nonetheless, prolactin (PRL), which belongs to the same family, has not been investigated in depth during embryonic and fetal development. PRL, similar to growth hormone and placental lactogen, may be involved in critical functions during such stages because of the highly conserved characteristics of this family of peptide hormones, including molecular weight, the number of amino acid residues, and structural homologies. Also, these hormones share analog functions and receptor positions [1]. All these data suggest a role of PRL in the regulation of early vertebrate development. Indeed, excellent reviews on the molecular and physiological functions of PRL centered on postnatal and adult processes (e.g., lactation, reproduction, neuroprotection and maternal behavior) have been published [2-6]. Thus, despite being a hormone with several physiological actions, scarce information about its role during embryonic and fetal development has been published. Herein, we analyze the physiological action of PRL during preimplantation stages, i.e., oocyte maturation, fecundation and early blastocyst formation, with a focus on pluripotency and diapause. Also, we evaluate its function in neural stem cells during the early nervous system development. PROLACTIN AND ITS RECEPTOR Generalities Prolactin (PRL) is a physiological hormone discovered in 1928 and first reported in 1933 by Oscar Riddle and coworkers [7] . Together with the growth hormone and placental lactogen, PRL belongs to the Class-I helical cytokine superfamily. These cytokines emerged from genetic duplications during early vertebrate evolution and are similar in their exon organization, amino acid sequences, tertiary structures and receptor-union properties. They also share 25-30% of their amino acid sequence identity and display considerable differences throughout evolution [8, 9] . The mouse and human PRL gene (approximate 10kb) are in chromosomes 13 and 6, respectively. It consists of five exons and four introns, which transcribe a 200 amino acids peptide with an approximate molecular mass of 23 kDa [10] [11] [12] [13] . Two promoters regulate its transcription, the 1b exon in the adenohypophysis regulated by Pit1 (PouF1, POU class 1 homeobox 1) and the non-coding 1a exon in extra-hypophysis tissues [14] [15] [16] . In all species except for fish, the PRL monomer has three cysteines related to the formation of three disulfide bridges and the result of such interactions produce the secondary structure of the hormone (α-helix united by disulfide bridges and the rest forming loops) (Fig. 1) [17, 14, 18] . Processes like alternative splicing and post-translational modifications (proteolytic cleavage, dimerization, phosphorylation and glycosylation) take place during the hormone maturation throughout the endoplasmic reticulum, Golgi apparatus and secretory granules, impacting the structure and function of the hormone due to changes in receptor affinity and cytosolic distribution [8, 19, 20] . The hormone exerts over 300 physiological actions, more than all other pituitary hormones combined [21, 22, 14] . This versatility in vertebrates encompasses six categories: 1) reproduction and lactation, 2) water and electrolyte balance, 3) morphogenesis and growth, 4) metabolism, 5) behavior and 6) immunoregulation (Fig. 1) [23, 14, 9] . PRL sources distribute extensively in the anterior pituitary, thymus, spleen, brain, ovaries, myometrium and decidua. Moreover, the PRL receptor (PRLr) is broadly found in the mammary
doi:10.1159/000516939 pmid:33934093 fatcat:pwfl3nqxznfofnwpbzjbnt4dbe