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dc.contributor.author
Ramaswamy, Suresh
dc.contributor.author
Walker, William H.
dc.contributor.author
Aliberti, Paula
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dc.contributor.author
Sethi, Rahil
dc.contributor.author
Marshall, Gary R.
dc.contributor.author
Smith, Alyxzandria
dc.contributor.author
Nourashrafeddin, Seyedmehdi
dc.contributor.author
Belgorosky, Alicia
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dc.contributor.author
Chandran, Uma R.
dc.contributor.author
Hedger, Mark P.
dc.contributor.author
Plant, Tony M.
dc.date.available
2019-03-21T22:22:44Z
dc.date.issued
2017-10
dc.identifier.citation
Ramaswamy, Suresh; Walker, William H.; Aliberti, Paula; Sethi, Rahil; Marshall, Gary R.; et al.; The testicular transcriptome associated with spermatogonia differentiation initiated by gonadotrophin stimulation in the juvenile rhesus monkey (Macaca mulatta); Oxford University Press; Human Reproduction; 32; 10; 10-2017; 2088-2100
dc.identifier.issn
0268-1161
dc.identifier.uri
http://hdl.handle.net/11336/72271
dc.description.abstract
STUDY QUESTION What is the genetic landscape within the testis of the juvenile rhesus monkey (Macaca mulatta) that underlies the decision of undifferentiated spermatogonia to commit to a pathway of differentiation when puberty is induced prematurely by exogenous LH and FSH stimulation? SUMMARY ANSWER Forty-eight hours of gonadotrophin stimulation of the juvenile monkey testis resulted in the appearance of differentiating B spermatogonia and the emergence of 1362 up-regulated and 225 down-regulated testicular mRNAs encoding a complex network of proteins ranging from enzymes regulating Leydig cell steroidogenesis to membrane receptors, and from juxtacrine and paracrine factors to transcriptional factors governing spermatogonial stem cell fate. WHAT IS KNOWN ALREADY Our understanding of the cell and molecular biology underlying the fate of undifferentiated spermatogonia is based largely on studies of rodents, particularly of mice, but in the case of primates very little is known. The present study represents the first attempt to comprehensively address this question in a highly evolved primate. STUDY DESIGN, SIZE, DURATION Global gene expression in the testis from juvenile rhesus monkeys that had been stimulated with recombinant monkey LH and FSH for 48 h (N = 3) or 96 h (N = 4) was compared to that from vehicle treated animals (N = 3). Testicular cell types and testosterone secretion were also monitored. PARTICIPANTS/MATERIALS, SETTING, METHODS Precocious testicular puberty was initiated in juvenile rhesus monkeys, 14-24 months of age, using a physiologic mode of intermittent stimulation with i.v. recombinant monkey LH and FSH that within 48 h produced â adult' levels of circulating LH, FSH and testosterone. Mitotic activity was monitored by immunohistochemical assays of 5-bromo-2′-deoxyuridine and 5-ethynyl-2′-deoxyuridine incorporation. Animals were bilaterally castrated and RNA was extracted from the right testis. Global gene expression was determined using RNA-Seq. Differentially expressed genes (DEGs) were identified and evaluated by pathway analysis. mRNAs of particular interest were also quantitated using quantitative RT-PCR. Fractions of the left testis were used for histochemistry or immunoflouresence. MAIN RESULTS AND THE ROLE OF CHANCE Differentiating type B spematogonia were observed after both 48 and 96 h of gonadotrophin stimulation. Pathway analysis identified five super categories of over-represented DEGs. Repression of GFRA1 (glial cell line-derived neurotrophic factor family receptor alpha 1) and NANOS2 (nanos C2HC-type zinc finger 2) that favor spermatogonial stem cell renewal was noted after 48 and 96 h of LH and FSH stimulation. Additionally, changes in expression of numerous genes involved in regulating the Notch pathway, cell adhesion, structural plasticity and modulating the immune system were observed. Induction of genes associated with the differentiation of spermatogonia stem cells (SOHLH1(spermatogenesis- A nd oogenesis-specific basic helix-loop-helix 1), SOHLH2 and KIT (V-Kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog)) was not observed. Expression of the gene encoding STRA8 (stimulated by retinoic acid 8), a protein generally considered to mark activation of retinoic acid signaling, was below our limit of detection. LARGE SCALE DATA The entire mRNA data set for vehicle and gonadotrophin treated animals (N = 10) has been deposited in the GEO-NCBI repository (GSE97786). LIMITATIONS REASONS FOR CAUTION The limited number of monkeys per group and the dilution of low abundance germ cell transcripts by mRNAs contributed from somatic cells likely resulted in an underestimation of the number of differentially expressed germ cell genes. WIDER IMPLICATIONS OF THE FINDINGS The findings that expression of GDNF (a major promoter of spermatogonial stem cell renewal) was not detected in the control juvenile testes, expression of SOHLH1, SOHLH2 and KIT, promoters of spermatogonial differentiation in mice, were not up-regulated in association with the gonadotrophin-induced generation of differentiating spermatogonia, and that robust activation of the retinoic acid signaling pathway was not observed, could not have been predicted. These unexpected results underline the importance of non-human primate models in translating data derived from animal research to the human situation.
dc.format
application/pdf
dc.language.iso
eng
dc.publisher
Oxford University Press
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dc.rights
info:eu-repo/semantics/openAccess
dc.rights.uri
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
dc.subject
Differentiation
dc.subject
Glial Cell Line-Derived Neurotrophic Factor Family Receptor Alpha 1
dc.subject
Global Gene Expression
dc.subject
Gonadotrophin
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Retinoic Acid
dc.subject
Rhesus Monkey
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Rna-Seq
dc.subject
Spermatogenesis- a Nd Oogenesis-Specific Basic Helix-Loop-Helix 1
dc.subject
Spermatogonia
dc.subject
Testis
dc.subject.classification
Otras Medicina Clínica
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dc.subject.classification
Medicina Clínica
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dc.subject.classification
CIENCIAS MÉDICAS Y DE LA SALUD
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dc.title
The testicular transcriptome associated with spermatogonia differentiation initiated by gonadotrophin stimulation in the juvenile rhesus monkey (Macaca mulatta)
dc.type
info:eu-repo/semantics/article
dc.type
info:ar-repo/semantics/artículo
dc.type
info:eu-repo/semantics/publishedVersion
dc.date.updated
2019-03-20T13:35:43Z
dc.journal.volume
32
dc.journal.number
10
dc.journal.pagination
2088-2100
dc.journal.pais
Reino Unido
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dc.journal.ciudad
Oxford
dc.description.fil
Fil: Ramaswamy, Suresh. University of Pittsburgh at Johnstown; Estados Unidos. University of Pittsburgh; Estados Unidos
dc.description.fil
Fil: Walker, William H.. University of Pittsburgh; Estados Unidos. University of Pittsburgh at Johnstown; Estados Unidos
dc.description.fil
Fil: Aliberti, Paula. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
dc.description.fil
Fil: Sethi, Rahil. University of Pittsburgh; Estados Unidos. University of Pittsburgh at Johnstown; Estados Unidos
dc.description.fil
Fil: Marshall, Gary R.. No especifíca;
dc.description.fil
Fil: Smith, Alyxzandria. University of Pittsburgh; Estados Unidos. University of Pittsburgh at Johnstown; Estados Unidos
dc.description.fil
Fil: Nourashrafeddin, Seyedmehdi. University of Pittsburgh at Johnstown; Estados Unidos. University of Pittsburgh; Estados Unidos
dc.description.fil
Fil: Belgorosky, Alicia. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
dc.description.fil
Fil: Chandran, Uma R.. University of Pittsburgh; Estados Unidos. University of Pittsburgh at Johnstown; Estados Unidos
dc.description.fil
Fil: Hedger, Mark P.. Hudson Institute Of Medical Research; Australia
dc.description.fil
Fil: Plant, Tony M.. University of Pittsburgh; Estados Unidos. University of Pittsburgh at Johnstown; Estados Unidos
dc.journal.title
Human Reproduction
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dc.relation.alternativeid
info:eu-repo/semantics/altIdentifier/doi/http://dx.doi.org/10.1093/humrep/dex270
dc.relation.alternativeid
info:eu-repo/semantics/altIdentifier/url/https://academic.oup.com/humrep/article/32/10/2088/4098165
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