Laboratory of Developmental Neuroendocrinology
Prof. Roberto Maggi, PA email@example.com
The Developmental Neuroendocrinology lab organizes activities on different research areas, including:
- Investigation on the mechanisms involved in the migration and differentiation of GnRH neurons and their role in the pathogenesis of hypogonadotropic hypogonadisms.
- Study of neural hypothalamic stem cells
- Study of cancer stem cells in the molecular mechanisms involved in pathogenesis or progression of neuroblastoma tumors
- The main area of research of the laboratory is the neuroendocrinology of the reproductive system. Current works include the use of ‘ex vivo’ and ‘in vitro’ models to investigate the mechanisms controlling the development, the migratory activity and the differentiation of the Gonadotropin-Releasing Hormone neurons as pathogenic factors of Kallmann’s syndrome and, more in general, hypogonadotropic hypogonadism (HH), a family of genetic diseases characterized by infertility and anosmia. Targeting of olfactory axons to the olfactory bulb and migration of neurons secreting the hypothalamic gonadotropin-releasing hormone (GnRH) are impaired in HH. By ‘ex vivo’ experiments in knock-out and transgenic mice we are searching for new candidate genes/factors involved in the control of the development of GnRH neurons. Two cell lines (GT1 and GN) of immortalized GnRH neurons are used as ‘in vitro’ models of non-migrating and migrating neurons, respectively to analyze and characterize the identified factors GnRH neurons in controlled culture conditions.
- The neuroendocrine hypothalamus contains two distinct subsystems, the parvicellular and magnocellular neuronal systems, however, the molecular pathways that mediate the development of such neurons are largely unknown. The study of neural stem cells (NSC) offers a useful model to investigate such mechanisms. We recently setup and characterized of a pure stable cell line of NSC from E12 fetal mouse hypothalamus (AC1) that grows as a monolayer in continuous expansion and shows the ability to develop neuroendocrine lineages in vitro. This will help to elucidate the mechanisms involved in the specific differentiation of neurohormonal hypothalamic neurons as well as other physiological hypothalamic developmental processes.
- Neuroblastoma (NB) is the most common cancer of childhood derived from precursor cells of the sympathetic nervous system with an unfavorable prognosis often due to multidrug resistance with recurrence of the disease. Cancer stem cells (CSC) seem to be responsible for development, long-term maintenance and drug resistance of many human tumors; the possible therapy of NB could benefit from the study of this specific cell subpopulation. The lab is involved in an advanced study on the isolation and characterization of NB-CSC obtained by human NB cells grown in nude mice under chemotherapy drug selection.
- Neuronal cells ‘in vitro’ cultures
- ‘In vitro’ assays for cell migration, adhesion, proliferation and survival
- Gene expression analysis (PCR, real time PCR)
- Immunocytochemistry, immunohystochemistry, immunofluorescence
- ‘Ex vivo’ analysis of neuronal migration by histology techniques and fluorescent probes
- A. Cariboni, F. Pimpinelli, S. Colamarino, R. Zaninetti, M. Piccolella, C. Rumio, F. Piva, E. Rugarli, R. Maggi. (2004) The product of X-linked Kallmann's syndrome gene (KAL1) affects the migratory activity of Gonadotropin-Releasing Hormone (GnRH)-producing neurons. Hum Mol Gen 13:2781-2791
- A. Cariboni, R. Maggi (2006) Kallmann's syndrome, a neuronal migration defect. Cell Mol Life Sci 63:2512-2526
- P. Magni, E. Dozio E, M Ruscica, H. Watanobe, A. Cariboni, R. Zaninetti, M. Motta, R. Maggi (2007) Leukemia Inhibitory Factor Induces the Chemomigration of Immortalized Gonadotropin-Releasing Hormone Neurons through the Independent Activation of the Jak/STAT3, MAPK/ERK1/2 and PI3-K/Akt Signalling Pathways. Mol Endocrinol 21:1163-1174
- A. Cariboni, R. Maggi, JG Parnavelas (2007) From nose to fertility: the long migratory journey of gonadotropin-releasing hormone neurons. Trends Neurosci 30:638-644
- 5. R. Zaninetti, S. Tacchi , J. Erriquez, C.Distasi, R. Maggi, A. Cariboni, F. Condorelli, PL. Canonico, AA Genazzani (2008) Calcineurin Primes Immature GnRH-Secreting Neuroendocrine Cells for Migration. Mol Endocrinol 22:729-736
- 6. E. Messi, M. Florian, C. Caccia, M. Zanisi, R. Maggi. (2008) Retinoic acid reduces human neuroblastoma cell migration and invasiveness: effects on DCX, LIS1, neurofilaments-68 and vimentin expression. BMC Cancer 8:doi:10.1186/1471-2407-1188-1130
- A. Cariboni, K. Davidson, S. Rakic, R. Maggi, J.G. Parnavelas, C. Ruhrberg. (2011) Defective gonadotropin-releasing hormone neuron migration in mice lacking SEMA3A signalling through NRP1 and NRP2: implications for the aetiology of hypogonadotropic hypogonadism. Hum Mol Genet. 20:336-44
- Cariboni A, Andrews WD, Memi F, Ypsilanti AR, Zelina P, Chedotal A, Parnavelas JG. (2012) Slit2 and Robo3 modulate the migration of GnRH-secreting neurons. Development. Sep;139 (18):3326-31
- 9. Jayakody SA, Andoniadou CL, Gaston-Massuet C, Signore M, Cariboni A, Bouloux PM, Le Tissier P, Pevny LH, Dattani MT, Martinez-Barbera JP. (2012) SOX2 regulates the hypothalamic-pituitary axis at multiple levels. J Clin Invest. Oct 1;122(10):3635-46.
- R. Maggi, D. Dondi, M. Piccolella, L.A. Casulari and L. Martini New insight on the molecular aspects of glucocorticoid effects in nervous system development. J Endocrinol Invest. 2013 Jun 10. [Epub ahead of print]