Transcription Factor GLIS3: A New and Critical Regulator of Postnatal Stages of Mouse Spermatogenesis

Abstract

In this study, we identify a novel and essential role for the Krüppel-like zinc finger transcription factor GLI-similar 3 (GLIS3) in the regulation of postnatal spermatogenesis. We show that GLIS3 is expressed in gonocytes, spermatogonial stem cells (SSCs) and spermatogonial progenitors (SPCs), but not in differentiated spermatogonia and later stages of spermatogenesis or in somatic cells. Spermatogenesis is greatly impaired in GLIS3 knockout mice. Loss of GLIS3 function causes a moderate reduction in the number of gonocytes, but greatly affects the generation of SSCs/SPCs, and as a consequence the development of spermatocytes. Gene expression profiling demonstrated that the expression of genes associated with undifferentiated spermatogonia was dramatically decreased in GLIS3-deficient mice and that the cytoplasmic-to-nuclear translocation of FOXO1, which marks the gonocyte-to-SSC transition and is necessary for SSC self-renewal, is inhibited. These observations suggest that GLIS3 promotes the gonocyte-to-SSC transition and is a critical regulator of the dynamics of early postnatal spermatogenesis.

GLIS3 is indispensable for TSH/TSHR-dependent thyroid hormone biosynthesis and follicular cell proliferation

“…Similar phenotypes have been observed in Glis3-deficient mice (29)(30)(31)(32)(33)(34)(35). Recently, an association was found between GLIS3 variants and congenital hypothyroidism (36).…”

“…The level of Glis3 expression in the thyroid gland was almost equivalent to that in pancreatic islets and neonatal testis ( Figure 1C), tissues in which Glis3 is highly expressed (31,33). Moreover, analysis of the (sub)cellular localization of GLIS3 protein in the thyroid of Glis3-EGFP mice showed that GLIS3-EGFP is not expressed in PECAM1 + endothelial cells ( Figure 1D), but is expressed only in the nucleus of cells staining positively for the thyroid follicular cell marker PAX8 ( Figure 1E).…”

“…The Glis3-EGFP mice (C57BL/6-Glis3 < tm3(Glis3-EGFP) Amj>), which express a GLIS3-EGFP fusion protein to monitor GLIS3 expression, and the Glis3-deficient (Glis3KO; C57BL/6-Glis3 < tm3(mCherry)Amj>) mice were described previously (31,33). Both mouse lines were backcrossed onto C57BL/6 for at least 6 generations.…”

“…RNA was extracted using a RNAqueous-Micro Kit (Thermo Fisher Scientific) according to the manufacturer's instructions, amplified, and labeled Cy3 as described in the NuGEN Ovation Pico WTA System protocol (NuGEN) for Agilent microarrays. Gene expression analysis was carried out using Agilent Whole Mouse Genome 4 × 44 Multiplex Format Oligo Arrays (Agilent Technologies) as described previously (31). Data obtained with the Agilent Feature Extraction software (v12) were further analyzed with OmicSoft Array Studio (version 7.0).…”

Emerging roles of GLIS3 in neonatal diabetes, type 1 and type 2 diabetes

“…GLIS3, interacting with its co-activator WW domain containing transcription regulator 1 (WWTR1), plays a critical role in maintaining proper renal functions (Kang et al 2009a). A recent report showed that GLIS3 is also involved in the early postnatal spermatogenesis in mice (Kang et al 2016a). In the present review, we will focus on GLIS3 and diabetes, summarizing its roles in monogenic neonatal diabetes (Table 1), T1D and T2D (Table 2), as well as the underlying mechanisms explored in animal models.…”