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Horm Metab Res 2016; 48(02): 77-82
DOI: 10.1055/s-0041-111699
Review
© Georg Thieme Verlag KG Stuttgart · New York

STAT3-Ser/Hes3 Signaling: A New Molecular Component of the Neuroendocrine System?

P. Nikolakopoulou
1   Department of Internal Medicine III, Technische Universität Dresden, Dresden, Germany
,
S. W. Poser
1   Department of Internal Medicine III, Technische Universität Dresden, Dresden, Germany
,
J. Masjkur
1   Department of Internal Medicine III, Technische Universität Dresden, Dresden, Germany
,
M. Fernandez Rubin de Celis
1   Department of Internal Medicine III, Technische Universität Dresden, Dresden, Germany
,
L. Toutouna
1   Department of Internal Medicine III, Technische Universität Dresden, Dresden, Germany
,
C. L. Andoniadou
2   Department of Craniofacial Development and Stem Cell Biology, King’s College London, UK
,
R. D. McKay
3   Lieber Institute for Brain Development, Baltimore, USA
,
G. Chrousos
4   1st Department of Pediatrics, University of Athens Medical School, Athens, Aghia Sophia Children’s Hospital, Athens, Greece
,
M. Ehrhart-Bornstein
1   Department of Internal Medicine III, Technische Universität Dresden, Dresden, Germany
,
S. R. Bornstein
1   Department of Internal Medicine III, Technische Universität Dresden, Dresden, Germany
,
A. Androutsellis-Theotokis
1   Department of Internal Medicine III, Technische Universität Dresden, Dresden, Germany
5   Center for Regenerative Therapies Dresden, Dresden, Germany
6   Department of Stem Cell Biology, Centre for Biomolecular Sciences, Division of Cancer and Stem Cells, School of Medicine, University of Nottingham, Nottingham, UK
› Author Affiliations
Further Information

Publication History

received 03 November 2015

accepted 16 December 2015

Publication Date:
19 January 2016 (online)

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Abstract

The endocrine system involves communication among different tissues in distinct organs, including the pancreas and components of the Hypothalamic-Pituitary-Adrenal Axis. The molecular mechanisms underlying these complex interactions are a subject of intense study as they may hold clues for the progression and treatment of a variety of metabolic and degenerative diseases. A plethora of signaling pathways, activated by hormones and other endocrine factors have been implicated in this communication. Recent advances in the stem cell field introduce a new level of complexity: adult progenitor cells appear to utilize distinct signaling pathways than the more mature cells in the tissue they co-reside. It is therefore important to elucidate the signal transduction requirements of adult progenitor cells in addition to those of mature cells. Recent evidence suggests that a common non-canonical signaling pathway regulates adult progenitors in several different tissues, rendering it as a potentially valuable starting point to explore their biology. The STAT3-Ser/Hes3 Signaling Axis was first identified as a major regulator of neural stem cells and, subsequently, cancer stem cells. In the endocrine/neuroendocrine system, this pathway operates on several levels, regulating other types of plastic cells: (a) it regulates pancreatic islet cell function and insulin release; (b) insulin in turn activates the pathway in broadly distributed neural progenitors and possibly also hypothalamic tanycytes, cells with important roles in the control of the adrenal gland; (c) adrenal progenitors themselves operate this pathway. The STAT3-Ser/Hes3 Signaling Axis therefore deserves additional research in the context of endocrinology.

Key words

STAT3 - Hes3 - stem cells
 

  • References

  • 1 Altman J. Are new neurons formed in the brains of adult mammals?. Science 1962; 135: 1127-1128
    CrossrefPubMedGoogle Scholar
  • 2 Kaplan MS, Hinds JW. Neurogenesis in the adult rat: electron microscopic analysis of light radioautographs. Science 1977; 197: 1092-1094
    CrossrefPubMedGoogle Scholar
  • 3 Kaplan MS. Neurogenesis in the 3-month-old rat visual cortex. J Comp Neurol 1981; 195: 323-338
    CrossrefPubMedGoogle Scholar
  • 4 Gould E, Reeves AJ, Graziano MS, Gross CG. Neurogenesis in the neocortex of adult primates. Science 1999; 286: 548-552
    CrossrefPubMedGoogle Scholar
  • 5 Eriksson PS, Perfilieva E, Bjork-Eriksson T, Alborn AM, Nordborg C, Peterson DA, Gage FH. Neurogenesis in the adult human hippocampus. Nat Med 1998; 4: 1313-1317
    CrossrefPubMedGoogle Scholar
  • 6 Gage FH. Neurogenesis in the adult brain. J Neurosci 2002; 22: 612-613
    PubMedGoogle Scholar
  • 7 Pera MF, Andrade J, Houssami S, Reubinoff B, Trounson A, Stanley EG, Ward-van Oostwaard D, Mummery C. Regulation of human embryonic stem cell differentiation by BMP-2 and its antagonist noggin. J Cell Sci 2004; 117: 1269-1280
    CrossrefPubMedGoogle Scholar
  • 8 Hockfield S, McKay RD. Identification of major cell classes in the developing mammalian nervous system. J Neurosci 1985; 5: 3310-3328
    PubMedGoogle Scholar
  • 9 Cattaneo E, McKay R. Identifying and manipulating neuronal stem cells. Trends Neurosci 1991; 14: 338-340
    CrossrefPubMedGoogle Scholar
  • 10 Sato N, Meijer L, Skaltsounis L, Greengard P, Brivanlou AH. Maintenance of pluripotency in human and mouse embryonic stem cells through activation of Wnt signaling by a pharmacological GSK-3-specific inhibitor. Nat Med 2004; 10: 55-63
    CrossrefPubMedGoogle Scholar
  • 11 Dimou L, Gotz M. Glial cells as progenitors and stem cells: new roles in the healthy and diseased brain. Physiol Rev 2014; 94: 709-737
    CrossrefPubMedGoogle Scholar
  • 12 Hermann DM, Peruzzotti-Jametti L, Schlechter J, Bernstock JD, Doeppner TR, Pluchino S. Neural precursor cells in the ischemic brain – integration, cellular crosstalk, and consequences for stroke recovery. Frontiers in cellular neuroscience 2014; 8: 291
    PubMedGoogle Scholar
  • 13 Sanchez Alvarado A, Yamanaka S. Rethinking differentiation: stem cells, regeneration, and plasticity. Cell 2014; 157: 110-119
    CrossrefPubMedGoogle Scholar
  • 14 Craig CG, Tropepe V, Morshead CM, Reynolds BA, Weiss S, van der Kooy D. In vivo growth factor expansion of endogenous subependymal neural precursor cell populations in the adult mouse brain. J Neurosci 1996; 16: 2649-2658
    PubMedGoogle Scholar
  • 15 Lim DA, Alvarez-Buylla A. Adult neural stem cells stake their ground. Trends Neurosci 2014; 37: 563-571
    CrossrefPubMedGoogle Scholar
  • 16 Androutsellis-Theotokis A, Leker RR, Soldner F, Hoeppner DJ, Ravin R, Poser SW, Rueger MA, Bae SK, Kittappa R, McKay RD. Notch signalling regulates stem cell numbers in vitro and in vivo. Nature 2006; 442: 823-826
    CrossrefPubMedGoogle Scholar
  • 17 Androutsellis-Theotokis A, Rueger MA, Mkhikian H, Korb E, McKay RD. Signaling pathways controlling neural stem cells slow progressive brain disease. Cold Spring Harb Symp Quant Biol 2008; 73: 403-410
    CrossrefPubMedGoogle Scholar
  • 18 Androutsellis-Theotokis A, Rueger MA, Park DM, Mkhikian H, Korb E, Poser SW, Walbridge S, Munasinghe J, Koretsky AP, Lonser RR, McKay RD. Targeting neural precursors in the adult brain rescues injured dopamine neurons. Proc Natl Acad Sci U S A 2009; 106: 13570-13575
    CrossrefPubMedGoogle Scholar
  • 19 Poser SW, Park DM, Androutsellis-Theotokis A. The STAT3-Ser/Hes3 signaling axis: an emerging regulator of endogenous regeneration and cancer growth. Front Physiol 2013; 4: 273
    PubMedGoogle Scholar
  • 20 Masjkur J, Levenfus I, Lange S, Arps-Forker C, Poser S, Qin N, Vukicevic V, Chavakis T, Eisenhofer G, Bornstein SR, Ehrhart-Bornstein M, Androutsellis-Theotokis A. A defined, controlled culture system for primary bovine chromaffin progenitors reveals novel biomarkers and modulators. Stem Cells Transl Med 2014; 3: 801-808
    CrossrefPubMedGoogle Scholar
  • 21 Bonni A, Sun Y, Nadal-Vicens M, Bhatt A, Frank DA, Rozovsky I, Stahl N, Yancopoulos GD, Greenberg ME. Regulation of gliogenesis in the central nervous system by the JAK-STAT signaling pathway. Science 1997; 278: 477-483
    CrossrefPubMedGoogle Scholar
  • 22 Rajan P, McKay RD. Multiple routes to astrocytic differentiation in the CNS. J Neurosci 1998; 18: 3620-3629
    PubMedGoogle Scholar
  • 23 Levy DE, Darnell Jr JE. Stats: transcriptional control and biological impact. Nat Rev Mol Cell Biol 2002; 3: 651-662
    CrossrefPubMedGoogle Scholar
  • 24 Androutsellis-Theotokis A, Chrousos GP, McKay RD, Decherney AH, Kino T. Expression profiles of the nuclear receptors and their transcriptional coregulators during differentiation of neural stem cells. Horm Metab Res 2013; 45: 159-168
    Article in Thieme ConnectPubMedGoogle Scholar
  • 25 Androutsellis-Theotokis A, Rueger MA, Park DM, Boyd JD, Padmanabhan R, Campanati L, Stewart CV, LeFranc Y, Plenz D, Walbridge S, Lonser RR, McKay RD. Angiogenic factors stimulate growth of adult neural stem cells. PLoS One 2010; 5: e9414
    CrossrefPubMedGoogle Scholar
  • 26 Androutsellis-Theotokis A, Walbridge S, Park DM, Lonser RR, McKay RD. Cholera toxin regulates a signaling pathway critical for the expansion of neural stem cell cultures from the fetal and adult rodent brains. PLoS One 2010; 5: e10841
    CrossrefPubMedGoogle Scholar
  • 27 Lobe CG. Expression of the helix-loop-helix factor, Hes3, during embryo development suggests a role in early midbrain-hindbrain patterning. Mech Dev 1997; 62: 227-237
    CrossrefPubMedGoogle Scholar
  • 28 Imayoshi I, Kageyama R. bHLH factors in self-renewal, multipotency, and fate choice of neural progenitor cells. Neuron 2014; 82: 9-23
    CrossrefPubMedGoogle Scholar
  • 29 Park DM, Jung J, Masjkur J, Makrogkikas S, Ebermann D, Saha S, Rogliano R, Paolillo N, Pacioni S, McKay RD, Poser S, Androutsellis-Theotokis A. Hes3 regulates cell number in cultures from glioblastoma multiforme with stem cell characteristics. Sci Rep 2013; 3: 1095
    PubMedGoogle Scholar
  • 30 Ohta S, Misawa A, Fukaya R, Inoue S, Kanemura Y, Okano H, Kawakami Y, Toda M. Macrophage migration inhibitory factor (MIF) promotes cell survival and proliferation of neural stem/progenitor cells. J Cell Sci 2012; 125: 3210-3220
    CrossrefPubMedGoogle Scholar
  • 31 Salewski RP, Buttigieg J, Mitchell RA, van der Kooy D, Nagy A, Fehlings MG. The generation of definitive neural stem cells from PiggyBac transposon-induced pluripotent stem cells can be enhanced by induction of the NOTCH signaling pathway. Stem Cells Dev 2012; 22: 383-396
    PubMedGoogle Scholar
  • 32 Cassady JP, D’Alessio AC, Sarkar S, Dani VS, Fan ZP, Ganz K, Roessler R, Sur M, Young RA, Jaenisch R. Direct lineage conversion of adult mouse liver cells and B lymphocytes to neural stem cells. Stem Cell Rep 2014; 3: 948-956
    CrossrefPubMedGoogle Scholar
  • 33 Ziegler AN, Levison SW, Wood TL. Insulin and IGF receptor signalling in neural-stem-cell homeostasis. Nat Rev Endocrinol 2015; 11: 161-170
    PubMedGoogle Scholar
  • 34 Masjkur J, Arps-Forker C, Poser SW, Nikolakopoulou P, Toutouna L, Chenna R, Chavakis T, Chatzigeorgiou A, Chen LS, Dubrovska A, Choudhary P, Uphues I, Mark M, Bornstein SR, Androutsellis-Theotokis A. Hes3 is expressed in the adult pancreatic islet and regulates gene expression, cell growth, and insulin release. J Biol Chem 2014; 289: 35503-35516
    CrossrefPubMedGoogle Scholar
  • 35 Poser SW, Chenoweth JG, Colantuoni C, Masjkur J, Chrousos G, Bornstein SR, McKay RD, Androutsellis-Theotokis A. Concise review: reprogramming, behind the scenes: noncanonical neural stem cell signaling pathways reveal new, unseen regulators of tissue plasticity with therapeutic implications. Stem Cells Transl Med 2015; 4: 1251-1257
    CrossrefPubMedGoogle Scholar
  • 36 Hatakeyama J, Bessho Y, Katoh K, Ookawara S, Fujioka M, Guillemot F, Kageyama R. Hes genes regulate size, shape and histogenesis of the nervous system by control of the timing of neural stem cell differentiation. Development 2004; 131: 5539-5550
    CrossrefPubMedGoogle Scholar
  • 37 Bachor TP, Suburo AM. Neural stem cells in the diabetic brain. Stem cells international 2012; 820790
    PubMedGoogle Scholar
  • 38 Masjkur J, Levenfus I, Lange S, Arps-Forker C, Poser S, Qin N, Vukicevic V, Chavakis T, Eisenhofer G, Bornstein SR, Ehrhart-Bornstein M, Androutsellis-Theotokis A. A defined, controlled culture system for primary bovine chromaffin progenitors reveals novel biomarkers and modulators. Stem Cells Transl Med 2014; 3: 801-808
    CrossrefPubMedGoogle Scholar
  • 39 Hirata H, Ohtsuka T, Bessho Y, Kageyama R. Generation of structurally and functionally distinct factors from the basic helix-loop-helix gene Hes3 by alternative first exons. J Biol Chem 2000; 275: 19083-19089
    CrossrefPubMedGoogle Scholar
  • 40 Laufer E, Kesper D, Vortkamp A, King P. Sonic hedgehog signaling during adrenal development. Mol Cell Endocrinol 2012; 351: 19-27
    CrossrefPubMedGoogle Scholar
  • 41 Bolborea M, Dale N. Hypothalamic tanycytes: potential roles in the control of feeding and energy balance. Trends Neurosci 2013; 36: 91-100
    CrossrefPubMedGoogle Scholar
  • 42 Xu Y, Tamamaki N, Noda T, Kimura K, Itokazu Y, Matsumoto N, Dezawa M, Ide C. Neurogenesis in the ependymal layer of the adult rat 3rd ventricle. Exp Neurol 2005; 192: 251-264
    CrossrefPubMedGoogle Scholar
  • 43 Lee DA, Bedont JL, Pak T, Wang H, Song J, Miranda-Angulo A, Takiar V, Charubhumi V, Balordi F, Takebayashi H, Aja S, Ford E, Fishell G, Blackshaw S. Tanycytes of the hypothalamic median eminence form a diet-responsive neurogenic niche. Nat Neurosci 2012; 15: 700-702
    CrossrefPubMedGoogle Scholar
  • 44 Li J, Tang Y, Cai D. IKKbeta/NF-kappaB disrupts adult hypothalamic neural stem cells to mediate a neurodegenerative mechanism of dietary obesity and pre-diabetes. Nat Cell Biol 2012; 14: 999-1012
    CrossrefPubMedGoogle Scholar
  • 45 Altman J, Bayer SA. Development of the diencephalon in the rat. I. Autoradiographic study of the time of origin and settling patterns of neurons of the hypothalamus. The J Comp Neurol 1978; 182: 945-971
    PubMedGoogle Scholar
  • 46 Altman J, Bayer SA. The development of the rat hypothalamus. Adv Anatom Embryol Cell Biol 1986; 100: 1-178
    PubMedGoogle Scholar
  • 47 Puelles L. Brain segmentation and forebrain development in amniotes. Brain Res Bull 2001; 55: 695-710
    CrossrefPubMedGoogle Scholar
  • 48 Maggi R, Zasso J, Conti L. Neurodevelopmental origin and adult neurogenesis of the neuroendocrine hypothalamus. Front Cell Neurosci 2014; 8: 440
    PubMedGoogle Scholar
  • 49 Zeltser LM, Seeley RJ, Tschop MH. Synaptic plasticity in neuronal circuits regulating energy balance. Nat Neurosci 2012; 15: 1336-1342
    CrossrefPubMedGoogle Scholar
  • 50 Gage FH. Mammalian neural stem cells. Science 2000; 287: 1433-1438
    CrossrefPubMedGoogle Scholar
  • 51 Suh H, Consiglio A, Ray J, Sawai T, D’Amour KA, Gage FH. In vivo fate analysis reveals the multipotent and self-renewal capacities of Sox2+neural stem cells in the adult hippocampus. Cell Stem Cell 2007; 1: 515-528
    CrossrefPubMedGoogle Scholar
  • 52 Rodriguez EM, Blazquez JL, Pastor FE, Pelaez B, Pena P, Peruzzo B, Amat P. Hypothalamic tanycytes: a key component of brain-endocrine interaction. Int Rev Cytol 2005; 247: 89-164
    CrossrefPubMedGoogle Scholar
  • 53 Mathew TC. Regional analysis of the ependyma of the third ventricle of rat by light and electron microscopy. Anatom Histol Embryol 2008; 37: 9-18
    PubMedGoogle Scholar
  • 54 Bradshaw RA. Rita Levi-Montalcini (1909–2012). Nature 2013; 493: 306-306
    CrossrefPubMedGoogle Scholar
  • 55 Morton GJ, Cummings DE, Baskin DG, Barsh GS, Schwartz MW. Central nervous system control of food intake and body weight. Nature 2006; 443: 289-295
    CrossrefPubMedGoogle Scholar
  • 56 Vigh B, Vigh-Teichmann I, Manzano e Silva MJ, van den Pol AN. Cerebrospinal fluid-contacting neurons of the central canal and terminal ventricle in various vertebrates. Cell Tissue Res 1983; 231: 615-621
    CrossrefPubMedGoogle Scholar
  • 57 Barrett P, Ivanova E, Graham ES, Ross AW, Wilson D, Ple H, Mercer JG, Ebling FJ, Schuhler S, Dupre SM, Loudon A, Morgan PJ. Photoperiodic regulation of cellular retinol binding protein, CRBP1 [corrected] and nestin in tanycytes of the third ventricle ependymal layer of the Siberian hamster. J Endocrinol 2006; 191: 687-698
    CrossrefPubMedGoogle Scholar
  • 58 Baroncini M, Allet C, Leroy D, Beauvillain JC, Francke JP, Prevot V. Morphological evidence for direct interaction between gonadotrophin-releasing hormone neurones and astroglial cells in the human hypothalamus. J Neuroendocrinol 2007; 19: 691-702
    CrossrefPubMedGoogle Scholar
  • 59 Wei LC, Shi M, Chen LW, Cao R, Zhang P, Chan YS. Nestin-containing cells express glial fibrillary acidic protein in the proliferative regions of central nervous system of postnatal developing and adult mice. Brain Res Develop Brain Res 2002; 139: 9-17
    PubMedGoogle Scholar
  • 60 Sidibe A, Mullier A, Chen P, Baroncini M, Boutin JA, Delagrange P, Prevot V, Jockers R. Expression of the orphan GPR50 protein in rodent and human dorsomedial hypothalamus, tanycytes and median eminence. J Pineal Res 2010; 48: 263-269
    CrossrefPubMedGoogle Scholar
  • 61 Bolborea M, Laran-Chich MP, Rasri K, Hildebrandt H, Govitrapong P, Simonneaux V, Pevet P, Steinlechner S, Klosen P. Melatonin controls photoperiodic changes in tanycyte vimentin and neural cell adhesion molecule expression in the Djungarian hamster (Phodopus sungorus). Endocrinology 2011; 152: 3871-3883
    CrossrefPubMedGoogle Scholar
  • 62 Chauvet N, Prieto M, Alonso G. Tanycytes present in the adult rat mediobasal hypothalamus support the regeneration of monoaminergic axons. Exp Neurol 1998; 151: 1-13
    CrossrefPubMedGoogle Scholar
  • 63 Saaltink DJ, Havik B, Verissimo CS, Lucassen PJ, Vreugdenhil E. Doublecortin and doublecortin-like are expressed in overlapping and non-overlapping neuronal cell population: implications for neurogenesis. J Comp Neurol 2012; 520: 2805-2823
    CrossrefPubMedGoogle Scholar
  • 64 Kokoeva MV, Yin H, Flier JS. Neurogenesis in the hypothalamus of adult mice: potential role in energy balance. Science 2005; 310: 679-683
    CrossrefPubMedGoogle Scholar
  • 65 Moraes JC, Coope A, Morari J, Cintra DE, Roman EA, Pauli JR, Romanatto T, Carvalheira JB, Oliveira AL, Saad MJ, Velloso LA. High-fat diet induces apoptosis of hypothalamic neurons. PLoS One 2009; 4: e5045
    CrossrefPubMedGoogle Scholar
  • 66 Purkayastha S, Cai D. Disruption of neurogenesis by hypothalamic inflammation in obesity or aging. Rev Endocr Metab Disord 2013; 14: 351-356
    CrossrefPubMedGoogle Scholar
  • 67 Cai D, Liu T. Hypothalamic inflammation: a double-edged sword to nutritional diseases. Ann N Y Acad Sci 2011; 1243: E1-E39
    CrossrefPubMedGoogle Scholar
  • 68 Haan N, Goodman T, Najdi-Samiei A, Stratford CM, Rice R, El Agha E, Bellusci S, Hajihosseini MK. Fgf10-expressing tanycytes add new neurons to the appetite/energy-balance regulating centers of the postnatal and adult hypothalamus. J Neurosci 2013; 33: 6170-6180
    CrossrefPubMedGoogle Scholar
  • 69 Robins SC, Stewart I, McNay DE, Taylor V, Giachino C, Goetz M, Ninkovic J, Briancon N, Maratos-Flier E, Flier JS, Kokoeva MV, Placzek M. alpha-Tanycytes of the adult hypothalamic third ventricle include distinct populations of FGF-responsive neural progenitors. Nat Commun 2013; 4: 2049
    PubMedGoogle Scholar
  • 70 Boersma GJ, Salton SR, Spritzer PM, Steele CT, Carbone DL. Models and mechanisms of metabolic regulation: genes, stress, and the HPA and HPG axes. Horm Metab Res 2012; 44: 598-606
    Article in Thieme ConnectPubMedGoogle Scholar
  • 71 Kullmann S, Heni M, Veit R, Scheffler K, Machann J, Haring HU, Fritsche A, Preissl H. Selective insulin resistance in homeostatic and cognitive control brain areas in overweight and obese adults. Diabetes Care 2015; 38: 1044-1050
    Google Scholar