Prolactin increases SMN expression and survival in a mouse model of severe spinal muscular atrophy via the STAT5 pathway
Faraz Farooq, Francisco Abadía Molina, Jeremiah Hadwen, Duncan MacKenzie, Luke Witherspoon, Matthew Osmond, Martin Holcik, Alex MacKenzie
Faraz Farooq, Francisco Abadía Molina, Jeremiah Hadwen, Duncan MacKenzie, Luke Witherspoon, Matthew Osmond, Martin Holcik, Alex MacKenzie
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Research Article

Prolactin increases SMN expression and survival in a mouse model of severe spinal muscular atrophy via the STAT5 pathway

Abstract

Spinal muscular atrophy (SMA) is an autosomal recessive neurodegenerative disease that is characterized by the loss of motor neurons, resulting in progressive muscle atrophy. It is caused by the loss of functional survival motor neuron (SMN) protein due to mutations or deletion in the SMN1 gene. A potential treatment strategy for SMA is to upregulate levels of SMN protein. Several agents that activate STAT5 in human and mouse cell lines enhance SMN expression from the SMN2 gene and can compensate, at least in part, for the loss of production of a functional protein from SMN1. Here, we have shown that prolactin (PRL) increases SMN levels via activation of the STAT5 pathway. PRL increased SMN mRNA and protein levels in cultured human and mouse neuronal cells. Administration of STAT5-specific siRNA blocked the effects of PRL, indicating that the PRL-induced transcriptional upregulation of the SMN-encoding gene was mediated by activation of STAT5. Furthermore, systemic administration of PRL to WT mice induced SMN expression in the brain and spinal cord. Critically, PRL treatment increased SMN levels, improved motor function, and enhanced survival in a mouse model of severe SMA. Our results confirm earlier work suggesting STAT5 pathway activators as potential therapeutic compounds for the treatment of SMA and identify PRL as one such promising agent.

Authors

Faraz Farooq, Francisco Abadía Molina, Jeremiah Hadwen, Duncan MacKenzie, Luke Witherspoon, Matthew Osmond, Martin Holcik, Alex MacKenzie

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Figure 1

PRL treatment upregulates SMN mRNA and protein in vitro.

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PRL treatment upregulates SMN mRNA and protein in vitro. NT2 or MN-1...
NT2 or MN-1 cells were treated with PRL (0, 25, 50, and 100 ng/ml) and then harvested at indicated intervals for RT-PCR or Western blot analyses. (A) Presence of PRLR in NT2 cells. (B) Quantification of SMN mRNA relative to β-actin in NT2 cells after PRL treatment (fold induction; the ratio at 0 hour was set as 1). Mean + SD of 3 independent experiments. (C) Representative Western blot showing effect of PRL on SMN protein in NT2 cells. (D) Densitometric quantification of SMN relative to β-actin is shown for NT2 cells. Mean + SD of 3 independent experiments. (E) Representative Western blot showing effect of PRL on SMN protein in MN-1 cells. (F) Densitometric quantifications of Smn relative to tubulin are shown for MN-1 cells. Mean + SD of 3 independent experiments.