Rbpj-κ mediated Notch signaling plays a critical role in development of hypothalamic Kisspeptin neurons

被引:28
作者
Biehl, Matthew J. [1 ]
Raetzman, Lori T. [1 ]
机构
[1] Univ Illinois, Dept Mol & Integrat Physiol, Urbana, IL 61801 USA
关键词
Notch; Kisspeptin; Arcuate; Neurogenesis; Pomc; Rbpj; ENHANCER-BINDING PROTEIN; KISS1; GENE-EXPRESSION; PERSISTENT EXPRESSION; MOUSE HYPOTHALAMUS; ACTIVATED NOTCH; HORMONE NEURONS; MESSENGER-RNA; POMC NEURONS; CELL FATE; BRAIN;
D O I
10.1016/j.ydbio.2015.08.016
中图分类号
Q [生物科学];
学科分类号
07 ; 0710 ; 09 ;
摘要
The mammalian arcuate nucleus (ARC) houses neurons critical for energy homeostasis and sexual maturation. Proopiomelanocortin (POMC) and Neuropeptide Y (NPY) neurons function to balance energy intake and Kisspeptin neurons are critical for the onset of puberty and reproductive function. While the physiological roles of these neurons have been well established, their development remains unclear. We have previously shown that Notch signaling plays an important role in cell fate within the ARC of mice. Active Notch signaling prevented neural progenitors from differentiating into feeding circuit neurons, whereas conditional loss of Notch signaling lead to a premature differentiation of these neurons. Presently, we hypothesized that Kisspeptin neurons would similarly be affected by Notch manipulation. To address this, we utilized mice with a conditional deletion of the Notch signaling co-factor Rbpj-kappa (Rbpj cKO), or mice persistently expressing the Notch1 intracellular domain (NICD tg) within Nkx2.1 expressing cells of the developing hypothalamus. Interestingly, we found that in both models, a lack of Kisspeptin neurons are observed. This suggests that Notch signaling must be properly titrated for formation of Kisspeptin neurons. These results led us to hypothesize that Kisspeptin neurons of the ARC may arise from a different lineage of intermediate progenitors than NPY neurons and that Notch was responsible for the fate choice between these neurons. To determine if Kisspeptin neurons of the ARC differentiate similarly through a Pomc intermediate, we utilized a genetic model expressing the tdTomato fluorescent protein in all cells that have ever expressed Pomc. We observed some Kisspeptin expressing neurons labeled with the Pomc reporter similar to NPY neurons, suggesting that these distinct neurons can arise from a common progenitor. Finally, we hypothesized that temporal differences leading to premature depletion of progenitors in cKO mice lead to our observed phenotype. Using a BrdU birthdating paradigm, we determined the percentage of NPY and Kisspeptin neurons born on embryonic days 11.5, 12.5, and 13.5. We found no difference in the timing of differentiation of either neuronal subtype, with a majority occurring at e11.5. Taken together, our findings suggest that active Notch signaling is an important molecular switch involved in instructing subpopulations of progenitor cells to differentiate into Kisspeptin neurons. (C) 2015 Elsevier Inc. All rights reserved.
引用
收藏
页码:235 / 246
页数:12
相关论文
共 86 条
[1]   DEVELOPMENT OF DIENCEPHALON IN RAT .3. ONTOGENY OF SPECIALIZED VENTRICULAR LININGS OF HYPOTHALAMIC THIRD VENTRICLE [J].
ALTMAN, J ;
BAYER, SA .
JOURNAL OF COMPARATIVE NEUROLOGY, 1978, 182 (04) :995-1015
[2]   MIGRATION AND DISTRIBUTION OF 2 POPULATIONS OF HIPPOCAMPAL GRANULE CELL PRECURSORS DURING THE PERINATAL AND POSTNATAL PERIODS [J].
ALTMAN, J ;
BAYER, SA .
JOURNAL OF COMPARATIVE NEUROLOGY, 1990, 301 (03) :365-381
[3]   Sonic hedgehog lineage in the mouse hypothalamus: from progenitor domains to hypothalamic regions [J].
Alvarez-Bolado, Gonzalo ;
Paul, Fabian A. ;
Blaess, Sandra .
NEURAL DEVELOPMENT, 2012, 7
[4]   Persistent expression of activated notch in the developing hypothalamus affects survival of pituitary progenitors and alters pituitary structure [J].
Aujla, Paven K. ;
Bogdanovic, Vedran ;
Naratadam, George T. ;
Raetzman, Lori T. .
DEVELOPMENTAL DYNAMICS, 2015, 244 (08) :921-934
[5]   Notch/Rbpjκ signaling regulates progenitor maintenance and differentiation of hypothalamic arcuate neurons [J].
Aujla, Paven K. ;
Naratadam, George T. ;
Xu, Liwen ;
Raetzman, Lori T. .
DEVELOPMENT, 2013, 140 (17) :3511-3521
[6]   The Notch ligand DLL4 specifically marks human hematoendothelial progenitors and regulates their hematopoietic fate [J].
Ayllon, V. ;
Bueno, C. ;
Ramos-Mejia, V. ;
Navarro-Montero, O. ;
Prieto, C. ;
Real, P. J. ;
Romero, T. ;
Garcia-Leon, M. J. ;
Toribio, M. L. ;
Bigas, A. ;
Menendez, P. .
LEUKEMIA, 2015, 29 (08) :1741-1753
[7]   Birthdates of the tyrosine hydroxylase immunoreactive neurons in the hypothalamus of male and female rats [J].
Balan, IS ;
Ugrumov, MV ;
Borisova, NA ;
Calas, A ;
Pilgrim, C ;
Reisert, I ;
Thibault, J .
NEUROENDOCRINOLOGY, 1996, 64 (06) :405-411
[8]   Leptin receptor signaling in is required for normal body POW neurons weight homeostasis [J].
Balthasar, N ;
Coppari, R ;
McMinn, J ;
Liu, SM ;
Lee, CE ;
Tang, V ;
Kenny, CD ;
McGovern, RA ;
Chua, SC ;
Elmquist, JK ;
Lowell, BB .
NEURON, 2004, 42 (06) :983-991
[9]   DEVELOPMENT OF GONADOTROPIN-RELEASING-HORMONE (GNRH) NEURON REGULATION IN THE FEMALE RAT [J].
BECUVILLALOBOS, D ;
LIBERTUN, C .
CELLULAR AND MOLECULAR NEUROBIOLOGY, 1995, 15 (01) :165-176
[10]   Notch signaling acts before cell division to promote asymmetric cleavage and cell fate of neural precursor cells [J].
Bhat, Krishna Moorthi .
SCIENCE SIGNALING, 2014, 7 (348) :ra101