Mating and Pregnancy Can Occur in Genetically Hypogonadal Mice with Preoptic Area Brain Grafts

Gibson, M.E.; Krieger, Dorothy T.; Charlton, H. M.; Zimmerman, Earl A.; Silverman, Ann‐Judith; Perlow, Mark J.

doi:10.1126/science.6382608

Cited by 183 publications

(62 citation statements)

References 25 publications

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“…Placement of pre-optic area (POA) grafts containing GnRH neurons close to the ME successfully restores reproductive function in the gnrh1 mutant hypogonadal mice, independently of the sex of the donor. As expected, success appears to rely on accession of GnRH axons to the ME (Gibson et al 1984;Charlton 2004). Anterior hypothalamic implants comprising the suprachiasmatic nucleus restore periodicity in animals rendered arrhythmic by hypothalamic lesions (Sollars et al 1995).…”

Section: Implantation In Homotypic Locationssupporting

confidence: 53%

Perspective on Stem Cells in Developmental Biology, with Special Reference to Neuroendocrine Systems

Rizzoti

Pires

Lovell‐Badge

2016

Stem Cells in Neuroendocrinology

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In the embryo, organs gradually take shape as tissue progenitors, proliferate, differentiate and are organised, via cellular interactions, in tri-dimensional functional structures. Most adult organs retain a cell population sharing important similarities with embryonic progenitors, which includes the ability to both selfrenew and to differentiate into the full range of the specialised cell types corresponding to the organ in which they reside. These two essential properties define them as adult stem cells (AdSC). Their characterization in different contexts provides a better understanding of cell turnover modalities for organ function, which is important for tumorigenesis, because adult tissue stem cells can give rise to cancer stem cells. However, it is also relevant to regenerative medicine, because stem cells can be transplanted or manipulated in vivo to restore missing cells. The successful reprogramming of somatic cells into induced pluripotent stem cells (iPSC) (Takahashi and Yamanaka, Cell 126:663-676, 2006), resembling pluripotent embryonic stem cells (ESC), opened alternative strategies for cell replacement. The required cell type can be differentiated in vitro from expandable progenitors and transplanted where required. This approach is particularly promising, because genetic defects can potentially be repaired in vitro prior to their engraftment; moreover, a large number of cells can be produced (Fox et al., Science 345:1247391, 2014). However, the transplanted cells have to be able to functionally integrate into the deficient organ. To potentially alleviate this problem, tri-dimensional culture systems have been recently developed where mini-organs, or organoids, can be obtained in vitro. These also represent unique models for disease modelling and drug screening (Huch and Koo, Development 142:3113-3125, 2015). Within neuroendocrine systems, the hypothalamo-pituitary axis has a crucial role for body homeostasis. It also regulates functions such as growth, reproduction, stress and, more generally, metabolism. The hypothalamus centralizes information from the periphery and other brain regions to regulate pituitary hormone secretions and to control appetite, sleep and aging. Its functions are exerted through secretion of neurohormones and manipulation of these could be of interest not only for the treatment of obesity and sleep disorders but also to alleviate aging-related conditions. Pituitary hormone deficiencies can originate from defects affecting the hypothalamus, pituitary, or both. Today these deficiencies are treated by substitution or replacement therapies, which are costly and have side effects. AdSC have recently been characterized in the hypothalamus and pituitary (Castinetti et al., Endocr Rev 32:453-471, 2011; Bolborea and Dale, Trends Neurosci 36:91-100, 2013). Moreover, hypothalamic neurons and pituitary endocrine cells have been differentiated in vitro from ESC and iPSC and successfully transplanted. These promising routes for development of regenerative medicine to restore ...

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Section: Implantation In Homotypic Locationssupporting

confidence: 53%

Perspective on Stem Cells in Developmental Biology, with Special Reference to Neuroendocrine Systems

Rizzoti

Pires

Lovell‐Badge

2016

Stem Cells in Neuroendocrinology

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“…Notable in this regard are findings in hypogonadal (hpg) mice, which are unable to synthesize the mature GnRH peptide because of a deletion in the GnRH gene. The fertility of these mice was restored by the successful transplantation of just one to three detectable GnRH neurons (13,14,24), revealing a high degree of redundancy in the number of GnRH neurons. Thus, although reduced, the number of GnRH neurons in CaR Ϫ/Ϫ mice was clearly sufficient to maintain reproduction under laboratory conditions.…”

Section: Discussionmentioning

confidence: 96%

Calcium receptor stimulates chemotaxis and secretion of MCP-1 in GnRH neurons in vitro: potential impact on reduced GnRH neuron population in CaR-null mice

Chattopadhyay¹,

Jeong²,

Yano³

et al. 2007

American Journal of Physiology-Endocrinology and Metabolism

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The factors controlling the migration of mammalian gonadotropin-releasing hormone (GnRH) neurons from the nasal placode to the hypothalamus are not well understood. We studied whether the extracellular calcium-sensing receptor (CaR) promotes migration/chemotaxis of GnRH neurons. We demonstrated expression of CaR in GnRH neurons in the murine basal forebrain and in two GnRH neuronal cell lines: GT1-7 (hypothalamus derived) and GN11 (olfactory bulb derived). Elevated extracellular Ca2+concentrations promoted chemotaxis of both cell types, with a greater effect in GN11 cells. This effect was CaR mediated, as, in both cell types, overexpression of a dominant-negative CaR attenuated high Ca2+-stimulated chemotaxis. We also demonstrated expression of a β-chemokine, monocyte chemoattractant protein-1 (MCP-1), and its receptor, CC motif receptor-2 (CCR2), in the hypothalamic GnRH neurons as well as in GT1-7 and GN11 cells. Exogenous MCP-1 stimulated chemotaxis of both cell lines in a dose-dependent fashion; the effect was greater in GN11 than in GT1-7 cells, consistent with the higher CCR2 mRNA levels in GN11 cells. Activating the CaR stimulated MCP-1 secretion in GT1-7 but not in GN11 cells. MCP-1 secreted in response to CaR stimulation is biologically active, as conditioned medium from GT1-7 cells treated with high Ca2+promoted chemotaxis of GN11 cells, and this effect was partially attenuated by a neutralizing antibody to MCP-1. Finally, in the preoptic area of anterior hypothalamus, the number of GnRH neurons was ∼27% lower in CaR-null mice than in mice expressing the CaR gene. We conclude that the CaR may be a novel regulator of GnRH neuronal migration likely involving, in part, MCP-1.

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“…The possibility of heterologous input is strengthened by our recent observations that PNMT-positive fibers of the host enter the transplant in great abundance (E. A. Zimmerman, unpublished observations). Synapses that integrate the implant with the host CNS and that presumably also occur in grafts in female hosts might form part of the circuitry for the mating "induced" (stimulated) ovulations that can occur in these mice (Gibson et al, 1984b). A detailed quantitative comparison between the synaptic input for GnRH neurons in normal mouse preoptic area versus that for such neurons within the transplants is necessary to determine if the number and kind of synapses are similar in each.…”

Section: Discussionmentioning

confidence: 99%

“…When placed in the third ventricle, grafts of normal fetal preoptic area-the region containing the majority of GnRH neurons in rodents (Witkin et al, 1982)-can reverse the endocrine deficiencies ofboth male (Krieger et al, 1982) and female (Gibson et al, 1984a) hpghosts. In females receiving such replacement therapy, mating behavior and successful pregnancies can occur (Gibson et al, 1984b). Grafts generally contain a relatively small number of GnRH neurons, but GnRH fibers can exit into the host arcuate nucleus and median eminence .…”

mentioning

confidence: 99%

Ultrastructure of gonadotropin-releasing hormone neuronal structures derived from normal fetal preoptic area and transplanted into hypogonadal mutant (hpg) mice

Silverman¹,

Zimmerman²,

Kokoris³

et al. 1986

J. Neurosci.

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The hpg mutant mouse lacks the neurohormone gonadotropin-releasing hormone (GnRH) and hence has a reproductive deficit. This deficit can be corrected by placement of normal fetal preoptic area into the third ventricle (see Krieger et al., 1985). We have now used ultrastructural immunocytochemistry to investigate the morphology of GnRH neurons in such intraventricular grafts, the routes that their axons take as they exit into the host, and the neurosecretory terminations that they make in the host median eminence. The GnRH cells in the transplant were similar in morphology to that reported for such cells in the preoptic area of other rodents. There was a large central nucleus, frequently indented and containing 1 or 2 nucleoli. The thin rim of cytoplasm was filled with rough endoplasmic reticulum, Golgi stacks, and mitochondria. Both dendritic and axonal profiles were identified, and a modest synaptic input to the former was found. Between the host and the implant a complex multilayered ependymal zone developed, and it was through this region that GnRH axons exited into the host arcuate nucleus and median eminence, usually surrounded by ependymal or glial elements. Within the median eminence, GnRH terminals were in close association with fenestrated blood vessels forming a normal neurosecretory terminus.

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Mating and Pregnancy Can Occur in Genetically Hypogonadal Mice with Preoptic Area Brain Grafts

Cited by 183 publications

References 25 publications

Perspective on Stem Cells in Developmental Biology, with Special Reference to Neuroendocrine Systems

Perspective on Stem Cells in Developmental Biology, with Special Reference to Neuroendocrine Systems

Calcium receptor stimulates chemotaxis and secretion of MCP-1 in GnRH neurons in vitro: potential impact on reduced GnRH neuron population in CaR-null mice

Ultrastructure of gonadotropin-releasing hormone neuronal structures derived from normal fetal preoptic area and transplanted into hypogonadal mutant (hpg) mice

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