title: Temporal-Spatial Establishment of Initial Niche for the Primary Spermatogonial Stem Cell Formation Is Determined by an ARID4B Regulatory Network.
abstract: During neonatal testis development, centrally located gonocytes migrate to basement membrane of the seminiferous cords, where physical contact with a niche established by Sertoli cells is essential for transition of gonocytes into spermatogonial stem cells (SSCs). To provide structural support and signaling stimuli for the gonocyte-to-SSC transition that occurs at a specific location during a finite phase, temporal-spatial establishment of the niche is critical. To date, the factors that guide Sertoli cells to establish the initial stem cell niche remain largely unknown. Using the Sertoli cell-specific Arid4b knockout (Arid4bSCKO) mice, we demonstrated that ablation of AT-rich interaction domain 4B (ARID4B) resulted in abnormal detachment of Sertoli cells from the basement membrane of seminiferous cords during the gonocyte-to-SSC transition phase, suggesting failure to establish a niche for the SSC formation. Without support by a niche environment, gonocytes showed disarranged cell distribution in the Arid4bSCKO testes and underwent apoptosis. The commitment of gonocytes to differentiate into the spermatogonial lineage was broken and the capability of SSCs to self-renew and differentiate was also impaired. Gene expression profiling revealed the molecular mechanisms responsible for the phenotypic changes in the Arid4bSCKO testes, by identifying genes important for stem cell niche function as downstream effectors of ARID4B, including genes that encode gap junction protein alpha-1, KIT ligand, anti-Müllerian hormone, Glial cell-line derived neurotrophic factor, inhibin alpha, inhibin beta, and cytochrome P450 family 26 subfamily b polypeptide 1. Our results identified ARID4B as a master regulator of a signaling network that governs the establishment of a niche during the critical gonocyte-to-SSC transition phase to control the fate of gonocytes and SSCs. Stem Cells 2017;35:1554-1565.
authors.affiliation: Department of Biochemistry and Molecular Medicine, The George Washington University, Washington, District of Columbia, USA.
authors.forename: Ray-Chang
authors.initials: RC
authors.lastname: Wu
authors.affiliation: Department of Biochemistry and Molecular Medicine, The George Washington University, Washington, District of Columbia, USA.
authors.forename: Yang
authors.initials: Y
authors.lastname: Zeng
authors.affiliation: Department of Biochemistry and Molecular Medicine, The George Washington University, Washington, District of Columbia, USA.
authors.forename: Yu-Fang
authors.initials: YF
authors.lastname: Chen
authors.affiliation: Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Rainer B
authors.initials: RB
authors.lastname: Lanz
authors.affiliation: Department of Biochemistry and Molecular Medicine, The George Washington University, Washington, District of Columbia, USA.
authors.forename: Mei-Yi
authors.identifier: 0000-0002-0183-976X
authors.initials: MY
authors.lastname: Wu
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis; D002454:Cell Differentiation; D019070:Cell Lineage; D000066673:Cell Self Renewal; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D015536:Down-Regulation / Q000235:genetics; D018507:Gene Expression Regulation, Developmental; D053263:Gene Regulatory Networks; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009928:Organ Specificity; D013093:Spermatogonia / Q000166:cytology*; D055153:Stem Cell Niche; D013234:Stem Cells / Q000166:cytology* / Q000378:metabolism*; D013737:Testis / Q000196:embryology / Q000378:metabolism; D013997:Time Factors
chemical_list: D004268:DNA-Binding Proteins; D051100:Glial Cell Line-Derived Neurotrophic Factor; C515305:Rbbp1l1 protein, mouse
keywords: AT-rich interaction domain 4B; Gonocyte; Sertoli cell; Spermatogonia; Spermatogonial stem cell niche