Neurotrophins acting via TRKB receptors activate the JAGGED1-NOTCH2 cell-cell communication pathway to facilitate early ovarian development.
Tropomyosin-related kinase (TRK) receptor B (TRKB) mediates the supportive actions of neurotrophin 4/5 and brain-derived neurotrophic factor on early ovarian follicle development. Absence of TRKB receptors reduces granulosa cell (GC) proliferation and delays follicle growth. In the present study, we offer mechanistic insights into this phenomenon. DNA array and quantitative PCR analysis of ovaries from TrkB-null mice revealed that by the end of the first week of postnatal life, Jagged1, Hes1, and Hey2 mRNA abundance is reduced in the absence of TRKB receptors. Although Jagged1 encodes a NOTCH receptor ligand, Hes1 and Hey2 are downstream targets of the JAGGED1-NOTCH2 signaling system. Jagged1 is predominantly expressed in oocytes, and the abundance of JAGGED1 is decreased in TrkB(-/-) oocytes. Lack of TRKB receptors also resulted in reduced expression of c-Myc, a NOTCH target gene that promotes entry into the cell cycle, but did not alter the expression of genes encoding core regulators of cell-cycle progression. Selective restoration of JAGGED1 synthesis in oocytes of TrkB(-/-) ovaries via lentiviral-mediated transfer of the Jagged1 gene under the control of the growth differentiation factor 9 (Gdf9) promoter rescued c-Myc expression, GC proliferation, and follicle growth. These results suggest that neurotrophins acting via TRKB receptors facilitate early follicle growth by supporting a JAGGED1-NOTCH2 oocyte-to-GC communication pathway, which promotes GC proliferation via a c-MYC-dependent mechanism.
Division of Neuroscience, Oregon National Primate Research Center/Oregon Health and Science University, 505 Northwest 185th Avenue, Beaverton, Oregon 97006, USA.
Mauricio D
MD
Dorfman
Bredford
B
Kerr
Cecilia
C
Garcia-Rudaz
Alfonso H
AH
Paredes
Gregory A
GA
Dissen
Sergio R
SR
Ojeda
D000818:Animals; D002135:Calcium-Binding Proteins / Q000378:metabolism*; D002450:Cell Communication / Q000502:physiology*; D002453:Cell Cycle / Q000235:genetics; D049109:Cell Proliferation; D005260:Female; D005786:Gene Expression Regulation / Q000502:physiology; D006107:Granulosa Cells / Q000166:cytology; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D000072100:Jagged-1 Protein; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009414:Nerve Growth Factors / Q000378:metabolism / Q000502:physiology*; D006080:Ovarian Follicle / Q000166:cytology; D010053:Ovary / Q000254:growth & development*; D051883:Receptor, Notch2 / Q000235:genetics / Q000378:metabolism*; D020813:Receptor, trkB / Q000378:metabolism / Q000502:physiology*; D000072099:Serrate-Jagged Proteins
D002135:Calcium-Binding Proteins; D036341:Intercellular Signaling Peptides and Proteins; C000606274:Jag1 protein, mouse; D000072100:Jagged-1 Protein; D008565:Membrane Proteins; D009414:Nerve Growth Factors; D051883:Receptor, Notch2; D000072099:Serrate-Jagged Proteins; D020813:Receptor, trkB