Abstract
The tumor suppressor gene Reversion-inducing cysteine-rich protein with Kazal motifs (Reck) encodes a membrane-anchored protease regulator expressed in multiple tissues in mouse embryos and is essential for embryonic development. In postnatal mice, however, physiological roles for the RECK protein remain unclear. We found in this study that Reck is abundantly expressed in growth hormone (GH)-producing cells (somatotrophs) in the anterior pituitary gland (AP). We also found that two types of viable Reck mutant mice, one with reduced RECK expression (Hypo mice) and the other with induced Reck deficiency from 10 days after birth (iKO mice treated with tamoxifen), exhibit common phenotypes including decreases in body size and plasma levels of insulin-like growth factor-1 (IGF1). To gain insights into the function of RECK in the AP, we characterized several somatotroph-associated molecules in the AP of these mice. Immunoreactivity of GH was greatly reduced in tamoxifen-treated iKO mice; in these mice, two membrane receptors involved in the stimulation of GH secretion [growth hormone secretagogue receptor (GHSR) and growth hormone releasing hormone receptor (GHRHR)] were decreased, however, their mRNAs were increased. Decrease in GHSR immunoreactivity and concomitant increase in its mRNA were also found in the other mutant line, Hypo. Furthermore, reduced immunoreactivity of growth hormone receptor (GHR) and concomitant increase in its mRNA was also found in the liver of Hypo mice. These results raise the possibility that RECK supports proper functioning of the GH/IGF1 axis in mice, thereby affecting their growth and metabolism.
Highlights
Reversion-inducing Cysteine-rich protein with Kazal motifs (RECK)was initially isolated as a transformation suppressor gene encoding a glycosylphosphatidylinositol (GPI)-anchored glycoprotein (Takahashi et al, 1998)
We found in this study that Reck is abundantly expressed in growth hormone (GH)-producing cells in the anterior pituitary gland (AP)
Reck-expressing cells are found in the arcuate nucleus of the hypothalamus (ARH) and AP in adult mice
Summary
Reversion-inducing Cysteine-rich protein with Kazal motifs (RECK)was initially isolated as a transformation suppressor gene encoding a glycosylphosphatidylinositol (GPI)-anchored glycoprotein (Takahashi et al, 1998). RECK expression is downregulated in a wide variety of tumors, leading to increases in their angiogenesis-inducing activity and their potential for invasion, metastasis, and recurrence (Noda and Takahashi, 2007; Hill et al, 2011; Shi et al, 2016). Reck-deficient mice die around embryonic day 10.5 (E10.5) with increased gelatinase activity in the tissue, decreased tissue integrity, and abnormalities in vascular and neural development Studies on the vascular phenotype of these mice revealed that RECK binds GPR124, an orphan. A study on the neural phenotype of Reck-deficient mice, revealed that RECK promotes Notch signaling required for proper neurogenesis by inhibiting protease-mediated shedding of Notch-ligands on adjacent cells (Muraguchi et al, 2007). The elucidation of physiological roles for RECK in postnatal life, had been hindered by the embryonic lethality of Reck-deficient mice
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