Procreation is essential for survival of species. Not surprisingly, complex neuronal networks have evolved to mediate the diverse internal and external environmental inputs that regulate reproduction in vertebrates. Ultimately, these regulatory factors impinge, directly or indirectly, on a final common pathway, the neurons producing the gonadotropin-releasing hormone (GnRH), which stimulates pituitary gonadotropin secretion and thereby gonadal function. Compelling evidence, accumulated in the last few years, has revealed that kisspeptins, a family of neuropeptides encoded by the Kiss1 gene and produced mainly by neuronal clusters at discrete hypothalamic nuclei, are pivotal upstream regulators of GnRH neurons. As such, kisspeptins have emerged as important gatekeepers of key aspects of reproductive maturation and function, from sexual differentiation of the brain and puberty onset to adult regulation of gonadotropin secretion and the metabolic control of fertility. This review aims to provide a comprehensive account of the state-of-the-art in the field of kisspeptin physiology by covering in-depth the consensus knowledge on the major molecular features, biological effects, and mechanisms of action of kisspeptins in mammals and, to a lesser extent, in nonmammalian vertebrates. This review will also address unsolved and contentious issues to set the scene for future research challenges in the area. By doing so, we aim to endow the reader with a critical and updated view of the physiological roles and potential translational relevance of kisspeptins in the integral control of reproductive function.

Kisspeptins and Reproduction: Physiological Roles and Regulatory Mechanisms

Identification of Multipotent Luminal Progenitor Cells in Human Prostate Organoid Cultures

Poly-ADP-ribose metabolism plays a mayor role in a wide range of biological processes, such as maintenance of genomic stability, transcriptional regulation, energy metabolism and cell death. Poly-ADP-ribose polymerases (PARPs) are an ancient family of enzymes, as evidenced by the poly-ADP-ribosylating activities reported in dinoflagellates and archaebacteria and by the identification of Parp-like genes in eubacterial and archaeabacterial genomes. Six genes encoding "bona fide" PARP enzymes have been identified in mammalians: PARP1, PARP2, PARP3, PARP4/vPARP, PARP5/Tankyrases-1 and PARP6/Tankyrases-2. The best studied of these enzymes PARP1 plays a primary role in the process of poly-ADP-ribosylation. PARP1-mediated poly-ADP-ribosylation has been implicated in the pathogenesis of cancer, inflammatory and neurodegenerative disorders. This review will summarize the novel findings and concepts for PARP enzymes and their poly-ADP-ribosylation activity in the regulation of physiological and pathophysiological processes. A special focus is placed on the proposed molecular mechanisms involved in these processes, such as signaling, regulation of telomere dynamics, remodeling of chromatin structure and transcriptional regulation. A potential functional cross talk between PARP family members and other NAD+-consuming enzymes is discussed.

The diverse biological roles of mammalian PARPS, a small but powerful family of poly-ADP-ribose polymerases.

Lgr5 was originally discovered as a common Wnt target gene in adult intestinal crypts and colon cancer. It was subsequently identified as an exquisite marker of multiple Wnt-driven adult stem cell types. Lgr5 and its homologs, Lgr4 and Lgr6, constitute the receptors for R-spondins, potent Wnt signal enhancers and stem cell growth factors. The Lgr5/R-spondin complex acts by neutralizing Rnf43 and Znrf3, two transmembrane E3 ligases that remove Wnt receptors from the stem cell surface. Rnf43/Znrf3 are themselves encoded by Wnt target genes and constitute a negative Wnt feedback loop. Thus, adult stem cells are controlled by an intricate interplay of potent Wnt agonists, antagonists, and anti-antagonists.

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The R-spondin/Lgr5/Rnf43 module: regulator of Wnt signal strength

The epithelial lining of the fallopian tube is of critical importance for human reproduction and has been implicated as a site of origin of high-grade serous ovarian cancer. Here we report on the establishment of long-term, stable 3D organoid cultures from human fallopian tubes, indicative of the presence of adult stem cells. We show that single epithelial stem cells in vitro can give rise to differentiated organoids containing ciliated and secretory cells. Continuous growth and differentiation of organoids depend on both Wnt and Notch paracrine signalling. Microarray analysis reveals that inhibition of Notch signalling causes downregulation of stem cell-associated genes in parallel with decreased proliferation and increased numbers of ciliated cells and that organoids also respond to oestradiol and progesterone treatment in a physiological manner. Thus, our organoid model provides a much-needed basis for future investigations of signalling routes involved in health and disease of the fallopian tube.

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The Notch and Wnt pathways regulate stemness and differentiation in human fallopian tube organoids.

Mechanisms modulating prostate cell fate determination remain unexplored The leucine-rich repeat containing G-protein-coupled receptors (Lgr) have been identified as important stem cell markers in various tissues Here, we investigated the roles of Lgr4/Gpr48 in prostate stem cells (PSCs) and development Lgr4 was ubiquitously expressed during early prostate development prior to lineage specification, with adult expression restricted to a few basal cells (principally Lin−Sca1+CD49f+) Lgr4−/− mice had compromised branching morphogenesis and delayed epithelial differentiation, leading to decreased prostate size and impaired luminal cell function In vitro prostate sphere culture revealed that Lgr4−/− Lin−/Sca1+/CD49f+ cells failed to generate p63low cells, indicating a differentiation deficiency Furthermore, Lgr4 ablation arrested PSC differentiation of in vivo kidney capsule prostate grafts, suggesting that Lgr4 modulates PSC properties independent of hormonal and mesenchymal effects Analysis of neonatal prostates and prostate spheres revealed a decrease in Wnt, Sonic Hedgehog, and Notch1 expression in Lgr4−/− cells Lgr4 loss blocked differentiation of prostate sphere p63hi cells to p63low Treatment with exogenous Sonic Hedgehog partially restored the differentiation of p63hi cells in Lgr4−/− spheres Taken together, our data revealed the roles of Lgr4 in early prostate development and in stem cell differentiation through regulation of the Wnt, Notch, and Sonic Hedgehog signaling pathways Stem Cells 2013;31:2492–2505

https://stemcellsjournals.onlinelibrary.wiley.com/doi/pdf/10.1002/stem.1484

Lgr4 is a key regulator of prostate development and prostate stem cell differentiation

Activation of KISS1 receptor (KISS1R or GPR54) by its ligands (Kisspeptins) regulates a diverse function both in normal physiology and pathophysiology. In cancer, KISS1R has been implicated in tumor angiogenesis and metastasis, but a broader evaluation of KISS1R in tumorigenesis and tumor progression is yet to be conducted. In this study, we used mouse models of Kiss1r gene knockout and mouse mammary tumor virus-polyoma virus middle T antigen (MMTV-PyMT)-induced breast cancer to conduct such an evaluation. Kiss1r heterozygosity in MMTV-PyMT mice was sufficient to attenuate breast cancer initiation, growth, latency, multiplicity, and lung metastasis. To confirm these effects and assess possible contributions of endogenous ligands, we isolated primary tumor cells from PyMT/Kiss1r(+/+) and PyMT/Kiss1r(+/-) mice and compared their phenotypes by in vitro and in vivo assays. Kiss1r loss attenuated in vitro tumorigenic properties as well as tumor growth in vivo in immunocompromised NOD.SCID/NCr mice. Kiss1r activation in these cells, resulting from the addition of its ligand Kisspeptin-10, resulted in RhoA activation and RhoA-dependent gene expression through the Gαq-p63RhoGEF signaling pathway. Anchorage-independent growth was tightly linked to dose-dependent regulation of RhoA by Kiss1r. In support of these results, siRNA-mediated knockdown of KISS1R or inactivation of RhoA in human MCF10A breast epithelial cells overexpressing H-RasV12 was sufficient to reduce Ras-induced anchorage-independent growth. In summary, we concluded that Kiss1r attenuation was sufficient to delay breast tumor initiation, progression, and metastasis through inhibitory effects on the downstream Gαq-p63RhoGEF-RhoA signaling pathway.

https://cancerres.aacrjournals.org/content/canres/early/2011/08/17/0008-5472.CAN-11-0329.full.pdf

Haploinsufficiency in the prometastasis Kiss1 Receptor Gpr54 delays breast tumor initiation, progression and lung metastasis

It has been reported that mouse Lbh (limb-bud and heart) can regulate cardiac gene expression by modulating the combinatorial activities of key cardiac transcription factors, as well as their individual functions in cardiogenesis. Here we report the cloning and characterization of the human homolog of mouse Lbh gene, hLBH, from a human embryonic heart cDNA library. The cDNA of hLBH is 2927 bp long, encoding a protein product of 105 amino acids. The protein is highly conserved in evolution across different species from zebra fish, to mouse, to human. Northern blot analysis indicates that a 2.9 kb transcript specific for hLBH is most abundantly expressed in both embryonic and adult heart tissue. In COS-7 cells, hLBH proteins are localized to both the nucleus and the cytoplasm. hLBH is a transcription activator when fused to Gal-4 DNA-binding domain. Deletion analysis indicates that both the N-terminal containing proline-dependent serine/threonine kinase group and the C-terminal containing ERK D-domain motif are required for transcriptional activation. Overexpression of hLBH in COS-7 cells activates the transcriptional activities of activator protein-1 (AP-1) and serum response element (SRE). These results suggest that hLBH proteins may act as a transcriptional activator in mitogen-activated protein kinase signaling pathway to mediate cellular functions.

A human homolog of mouse Lbh gene, hLBH, expresses in heart and activates SRE and AP-1 mediated MAPK signaling pathway.

KiSS1 and its cognate G-protein-coupled receptor, GPR54, have diverse functions. While KiSS1 and GPR54 have been intensively studied in physiology, their role in cancer is still unclear. In cancer, KiSS1 and GPR54 have been known to suppress metastasis by inhibiting cancer cell motility. However, recent studies suggest that KiSS1 and GPR54 have varied roles even in cancer development and metastasis. Here, we examine recent advances in understanding the roles of KiSS1 and GPR54 in cancer development and metastasis.

KiSS1 and its G-protein-coupled receptor GPR54 in cancer development and metastasis.

Regulation of Embryonic Kidney Branching Morphogenesis and Glomerular Development by KISS1 Receptor (Gpr54) through NFAT2- and Sp1-mediated Bmp7 Expression

Kunrong Tan

Papers

Lgr4 is a key regulator of prostate development and prostate stem cell differentiation

Haploinsufficiency in the prometastasis Kiss1 Receptor Gpr54 delays breast tumor initiation, progression and lung metastasis

A human homolog of mouse Lbh gene, hLBH, expresses in heart and activates SRE and AP-1 mediated MAPK signaling pathway.

KiSS1 and its G-protein-coupled receptor GPR54 in cancer development and metastasis.

Regulation of Embryonic Kidney Branching Morphogenesis and Glomerular Development by KISS1 Receptor (Gpr54) through NFAT2- and Sp1-mediated Bmp7 Expression