Src and phospho‐FAK kinases are activated by allopregnanolone promoting Schwann cell motility, morphology and myelination

Melfi, Simona; Guevara, Maria Magdalena Montt; Bonalume, Veronica; Ruscica, Massimiliano; Colciago, Alessandra; Simoncini, Tommaso; Magnaghi, Valerio

doi:10.1111/jnc.13951

Cited by 28 publications

(33 citation statements)

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“…In fact, Rho/ROCK is one of the most important pathways that favors GBM cell migration, as ROCK phosphorylation targets include essential proteins involved in actomyosin contraction [ 41 , 42 ]. Recently, reports show that 3α-THP promotes rat Schwann cell migration in culture [ 43 ], suggesting that the induction of ROCK expression should increase GBM cell migration.…”

Section: Discussionmentioning

confidence: 99%

Allopregnanolone Alters the Gene Expression Profile of Human Glioblastoma Cells

Zamora-Sánchez

Moral-Morales

Hernández-Vega

et al. 2018

IJMS

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Glioblastomas (GBM) are the most frequent and aggressive brain tumors. In these malignancies, progesterone (P4) promotes proliferation, migration, and invasion. The P4 metabolite allopregnanolone (3α-THP) similarly promotes cell proliferation in the U87 human GBM cell line. Here, we evaluated global changes in gene expression of U87 cells treated with 3α-THP, P4, and the 5α-reductase inhibitor, finasteride (F). 3α-THP modified the expression of 137 genes, while F changed 90. Besides, both steroids regulated the expression of 69 genes. After performing an over-representation analysis of gene ontology terms, we selected 10 genes whose products are cytoskeleton components, transcription factors, and proteins involved in the maintenance of DNA stability and replication to validate their expression changes by RT-qPCR. 3α-THP up-regulated six genes, two of them were also up-regulated by F. Two genes were up-regulated by P4 alone, however, such an effect was blocked by F when cells were treated with both steroids. The remaining genes were regulated by the combined treatments of 3α-THP + F or P4 + F. An in-silico analysis revealed that promoters of the six up-regulated genes by 3α-THP possess cyclic adenosine monophosphate (cAMP) responsive elements along with CCAAT/Enhancer binding protein alpha (CEBPα) binding sites. These findings suggest that P4 and 3α-THP regulate different sets of genes that participate in the growth of GBMs.

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Section: Discussionmentioning

confidence: 99%

Allopregnanolone Alters the Gene Expression Profile of Human Glioblastoma Cells

Zamora-Sánchez

Moral-Morales

Hernández-Vega

et al. 2018

IJMS

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“…), such as neuronal plasticity in normal brain function, and reduces anxiety and depression (Catenaccio et al, ; Locci and Pinna, ; Pineles et al, ). One important function of progesterone is the promotion of myelination by oligodendrocytes and Schwann cells (Palliser et al, ; Melfi et al, ). In peripheral nerves, progesterone is locally produced from pregnenolone by Schwann cells to promote myelination (Koenig et al, ).…”

Section: Progesterone and Prsmentioning

confidence: 99%

Progesterone Effects in the Nervous System

Theis

Theiß

2019

The Anatomical Record

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The sex hormone progesterone is mainly known as a key factor in establishing and maintaining pregnancy. In addition, progesterone has been shown to induce morphological changes in the central and peripheral nervous system by increasing dendrito-, spino-, and synaptogenesis in Purkinje cells (Wessel et al.: Cell Mol Life Sci (2014a) 1723-1740 and increasing axonal outgrowth in dorsal root ganglia (Olbrich et al.: Endocrinology (2013) 3784-3795). These effects mediated mainly by the classical progesterone receptors (PRs) A and B seem to be limited to young neurons. It may be assumed that microRNAs (miRNAs), which are potent regulators of nervous system maturation and degeneration, are also involved in the regulation of progesterone-mediated neuronal plasticity by altering the expression patterns of the corresponding PR A/B receptors (Theis and Theiss: Neural Regen Res (2015) 547-549, Pieczora et al.: Cerebellum (2017) 376-387). This review critically discusses current data on the neuroprotective effect of progesterone and its corresponding receptors in the nervous system, with possible regulatory processes by miRNAs. Preclinical studies on stroke and traumatic brain injury revealed neuroprotective and neuroregenerative effects of progesterone in the treatment of severe neurological diseases in animal models, but have so far failed in humans. In this context, the identification of specific miRNAs that regulate the expression of progesterone and PR could help to exploit the neuroprotective potential of progesterone for the treatment of various neurological disorders. The human nervous system is a highly complex tissue composed of neurons and glial cells with a limited ability to regenerate after lesion or degeneration. In particular, the loss of neurons, for example, due to aging processes, stroke, or traumatic brain injury (TBI), is mostly irreversible. The function of the degenerating neurons can be partially compensated by neighboring neurons, but astroglial-fibrotic scar formation minimizes neuronal regeneration .Progesterone, a sexual hormone, is mainly known for its key role in the female reproductive circuit and the maintenance of pregnancy. In this context, the fact that progesterone is also expressed in the male organism is often neglected (Schumacher et al., 2014). Besides this, Abbreviations: BBB = blood brain barrier; CNS = central nervous system; DRG = dorsal root ganglia; GABA = Gamma-amino butyric acid; miRNA = microRNA; NMDAR = N-Methyl-D-aspartate receptor; PC = Purkinje cells; PGRMC1 = progesterone receptor membrane component 1; PNS = peripheral nervous system; PR = progesterone receptor; SCI = spinal cord injury; TBI = traumatic brain injury

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“…Mice DRG and SC co-cultures were set up on poly--lysine (100 μg/ml)-laminin (2 μg/ml) coated Petri dishes as previously described for rat cultures [14] with minor changes. To this end, dissociated DRG neurons were plated on Petri as described above and incubated for 3 days in vitro (div), in presence of 10 μM AraC to avoid endogenous glial cell contamination.…”

Section: Drg and Sc Co-culture And In Vitro Myelinationmentioning

confidence: 99%

“…To evaluate the myelinating capability, which is a key functional output of SCs, we established a coculture system of SCs with DRG neurons [14]. This is a reliable method that allows fine manipulation of the microenvironment, together with the modelling and studying of the signalling mechanisms between PNS cells.…”

Section: Figmentioning

confidence: 99%

GABA-B1 Receptor-Null Schwann Cells Exhibit Compromised In Vitro Myelination

et al. 2018

Self Cite

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GABA-B receptors are important for Schwann cell (SC) commitment to a non-myelinating phenotype during development. However, the P0-GABA-B1 conditional knockout mice, lacking the GABA-B1 receptor specifically in SCs, also presented axon modifications, suggesting SC non-autonomous effects through the neuronal compartment. In this in vitro study, we evaluated whether the specific deletion of the GABA-B1 receptor in SCs may induce autonomous or non-autonomous cross-changes in sensory dorsal root ganglia (DRG) neurons. To this end, we performed an in vitro biomolecular and transcriptomic analysis of SC and DRG neuron primary cultures from P0-GABA-B1 mice. We found that cells from conditional P0-GABA-B1 mice exhibited proliferative, migratory and myelinating alterations. Moreover, we found transcriptomic changes in novel molecules that are involved in peripheral neuron-SC interaction.

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Src and phospho‐FAK kinases are activated by allopregnanolone promoting Schwann cell motility, morphology and myelination

Cited by 28 publications

References 50 publications

Allopregnanolone Alters the Gene Expression Profile of Human Glioblastoma Cells

Allopregnanolone Alters the Gene Expression Profile of Human Glioblastoma Cells

Progesterone Effects in the Nervous System

GABA-B1 Receptor-Null Schwann Cells Exhibit Compromised In Vitro Myelination

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