Abstract
Oligodendrocytes are the myelinating cells of the central nervous system (CNS). These cells arise during the embryonic development by the specification of the neural stem cells to oligodendroglial progenitor cells (OPC); newly formed OPC proliferate, migrate, differentiate, and mature to myelinating oligodendrocytes in the perinatal period. It is known that progesterone promotes the proliferation and differentiation of OPC in early postnatal life through the activation of the intracellular progesterone receptor (PR). Progesterone supports nerve myelination after spinal cord injury in adults. However, the role of progesterone in embryonic OPC differentiation as well as the specific PR isoform involved in progesterone actions in these cells is unknown. By using primary cultures obtained from the embryonic mouse spinal cord, we showed that embryonic OPC expresses both PR-A and PR-B isoforms. We found that progesterone increases the proliferation, differentiation, and myelination potential of embryonic OPC through its PR by upregulating the expression of oligodendroglial genes such as neuron/glia antigen 2 (NG2), sex determining region Y-box9 (SOX9), myelin basic protein (MBP), 2′,3′-cyclic-nucleotide 3′-phosphodiesterase (CNP1), and NK6 homeobox 1 (NKX 6.1). These effects are likely mediated by PR-B, as they are blocked by the silencing of this isoform. The results suggest that progesterone contributes to the process of oligodendrogenesis during prenatal life through specific activation of PR-B.
Highlights
The proliferation and migratory phenotype of early oligodendroglial progenitor cells (OPC) is maintained by the platelet-derived growth factor (PDGF) and the fibroblast growth factor 2 (FGF2) [7,12], whereas mitotic arrest and subsequent oligodendrocyte differentiation is promoted by several elements such as thyroid hormones [13,14], the ciliary neurotrophic factor (CNTF), the extracellular matrix component laminin α2, and the presence of neuronal activity [15,16,17]; final maturation to myelinating oligodendrocytes is induced by the upregulation of promyelinating genes such as the myelin basic protein (MBP), myelin proteolipid protein (PLP), and 20,30 -cyclic-nucleotide 30 -phosphodiesterase (CNP1) [17,18]
We studied the effects of progesterone and the role of progesterone receptor (PR) in the proliferation, differentiation, and myelination potential of OPC, as well the effects of progesterone on the regulation of genes associated with developmental oligodendrogenesis by using isolated OPC from the embryonic mouse spinal cord
Given that PR-B is a more potent transcription activator than PR-A, and because it was observed that the effects of progesterone in the proliferation and differentiation of the OPC were mediated by a genomic mechanism, the expression of PR-B was silenced by siRNA transfection in order to study the role of this isoform in the mouse OPC
Summary
Central nervous system (CNS) myelination is a process that begins in late stages of mammalian prenatal life and extends to adulthood [1,2]; the oligodendrocytes responsible of this process arise earlier in embryonic neurodevelopment by the specification of neural stem cells (NSC) into oligodendroglial progenitor cells (OPC) after the neurogenic phase [3], which occurs approximately on day 12.5 of the mouse embryonic development and between gestational weeks 16–18 in the human [4,5].The first site of OPC specification during mammalian neurodevelopment has been identified in the ventral region of the neural tube, in the prospective cervical portion of the spinal cord [4,6,7].In this region, after the first wave of generation of the motoneurons of the spinal cord, the morphogen sonic hedgehog (Shh) promotes the induction of the NSC into OPC by upregulating the expression of a transcriptional program associated to the oligodendroglial lineage [6,8]; among the upregulated genes in this early specification stage are the transcription factors sex determining region Y-box9/10 (Sox9/10), oligodendrocyte transcription factor 1/2 (Olig1/2), NK6 homeobox 1/2 (Nkx 6.1/6.2) and the receptor α for the platelet-derived growth factor (PDGFRa) [8,9,10]. The proliferation and migratory phenotype of early OPC is maintained by the platelet-derived growth factor (PDGF) and the fibroblast growth factor 2 (FGF2) [7,12], whereas mitotic arrest and subsequent oligodendrocyte differentiation is promoted by several elements such as thyroid hormones [13,14], the ciliary neurotrophic factor (CNTF), the extracellular matrix component laminin α2 (merosin), and the presence of neuronal activity [15,16,17]; final maturation to myelinating oligodendrocytes is induced by the upregulation of promyelinating genes such as the myelin basic protein (MBP), myelin proteolipid protein (PLP), and 20 ,30 -cyclic-nucleotide 30 -phosphodiesterase (CNP1) [17,18] Along with these elements, some studies have shown that progesterone has a role in developmental oligodendrogenesis and the myelination process [19]; because the main role of this hormone lies in the maintenance of pregnancy, progesterone is constitutively present in the maternal and embryo-fetal circulation throughout development [20], and continues to be synthesized in the CNS of both females and males after birth [21]. It regulates different functions such as neuroprotection, neurogenesis, neuronal plasticity, sexual behavior, mood, learning, and memory [22,23]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
