Constitutive activation of CTNNB1 results in a loss of spermatogonial stem cell activity in mice

Autor: Xiangfan Zhang, Alexandre Boyer, Guillaume St-Jean, Adrien Levasseur, Makoto C. Nagano, Nour Abou Nader, Derek Boerboom
Jazyk: angličtina
Rok vydání: 2021
Předmět:
0301 basic medicine
Male
Physiology
Cellular differentiation
Gene Expression
Biochemistry
Mice
0302 clinical medicine
Animal Cells
Reproductive Physiology
Testis
Medicine and Health Sciences
Promyelocytic Leukemia Zinc Finger Protein
Cell Cycle and Cell Division
Testes
beta Catenin
Multidisciplinary
Adult Germline Stem Cells
Chromosome Biology
Stem Cells
Wnt signaling pathway
Gene Expression Regulation
Developmental
Cell Differentiation
Animal Models
Cell biology
Meiosis
medicine.anatomical_structure
Experimental Organism Systems
Cell Processes
030220 oncology & carcinogenesis
Medicine
Stem cell
Cellular Types
Anatomy
Genital Anatomy
Germ cell
Research Article
Signal Transduction
Genetically modified mouse
endocrine system
Glial Cell Line-Derived Neurotrophic Factor Receptors
Science
Mouse Models
Biology
Research and Analysis Methods
03 medical and health sciences
Model Organisms
Protein Domains
medicine
Genetics
Homeobox
Animals
Humans
Spermatogenesis
Progenitor
Cell Proliferation
Cell growth
Reproductive System
Biology and Life Sciences
Proteins
Cell Biology
Sperm
Spermatogonia
Transplantation
Repressor Proteins
030104 developmental biology
Germ Cells
Animal Studies
Developmental Biology
Zdroj: PLoS ONE
PLoS ONE, Vol 16, Iss 5, p e0251911 (2021)
ISSN: 1932-6203
Popis: Spermatogenesis requires that a careful balance be maintained between the self-renewal of spermatogonial stem cells (SSCs) and their commitment to the developmental pathway through which they will differentiate into spermatozoa. Recently, a series of studies employing various in vivo and in vitro models have suggested a role of the wingless-related MMTV integration site gene family/beta-catenin (WNT/CTNNB1) pathway in determining the fate of SSCs. However, conflicting data have suggested that CTNNB1 signaling may either promote SSC self-renewal or differentiation. Here, we studied the effects of sustained CTNNB1 signaling in SSCs using the Ctnnb1tm1Mmt/+; Ddx4-CreTr/+ (ΔCtnnb1) mouse model, in which a stabilized form of CTNNB1 is expressed in all germ cells. ΔCtnnb1 mice were found to have reduced testis weights and partial germ cell loss by 4 months of age. Germ cell transplantation assays showed a 49% reduction in total functional SSC numbers in 8 month-old transgenic mice. In vitro, Thy1-positive undifferentiated spermatogonia from ΔCtnnb1 mice formed 57% fewer clusters, which was associated with decreased cell proliferation. A reduction in mRNA levels of genes associated with SSC maintenance (Bcl6b, Gfra1, Plzf) and increased levels for markers associated with progenitor and differentiating spermatogonia (Kit, Rarg, Sohlh1) were detected in these cluster cells. Furthermore, RNAseq performed on these clusters revealed a network of more than 900 genes regulated by CTNNB1, indicating that CTNNB1 is an important regulator of spermatogonial fate. Together, our data support the notion that CTNNB1 signaling promotes the transition of SSCs to undifferentiated progenitor spermatogonia at the expense of their self-renewal.
Databáze: OpenAIRE
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