title: Lack of protein 4.1G causes altered expression and localization of the cell adhesion molecule nectin-like 4 in testis and can cause male infertility.
abstract: Protein 4.1G is a member of the protein 4.1 family, which in general serves as adaptors linking transmembrane proteins to the cytoskeleton. 4.1G is thought to be widely expressed in many cells and tissues, but its function remains largely unknown. To explore the function of 4.1G in vivo, we generated 4.1G(-/-) mice and bred the mice in two backgrounds: C57BL/6 (B6) and 129/Sv (129) hybrids (B6-129) and inbred B6. Although the B6 4.1G(-/-) mice showed no obvious abnormalities, deficiency of 4.1G in B6-129 hybrids was associated with male infertility. Histological examinations of these 4.1G(-/-) mice revealed atrophy, impaired cell-cell contact and sloughing off of spermatogenic cells in seminiferous epithelium, and lack of mature spermatids in the epididymis. Ultrastructural examination revealed enlarged intercellular spaces between spermatogenic and Sertoli cells as well as the spermatid deformities. At the molecular level, 4.1G is associated with the nectin-like 4 (NECL4) adhesion molecule. Importantly, the expression of NECL4 was decreased, and the localization of NECL4 was altered in 4.1G(-/-) testis. Thus, our findings imply that 4.1G plays a role in spermatogenesis by mediating cell-cell adhesion between spermatogenic and Sertoli cells through its interaction with NECL4 on Sertoli cells. Additionally, the finding that infertility is present in B6-129 but not on the B6 background suggests the presence of a major modifier gene(s) that influences 4.1G function and is associated with male infertility.
authors.affiliation: Red Cell Physiology Laboratory, New York Blood Center, New York, New York 10065, USA.
authors.forename: Shaomin
authors.initials: S
authors.lastname: Yang
authors.forename: Haibo
authors.initials: H
authors.lastname: Weng
authors.forename: Lixiang
authors.initials: L
authors.lastname: Chen
authors.forename: Xinhua
authors.initials: X
authors.lastname: Guo
authors.forename: Marilyn
authors.initials: M
authors.lastname: Parra
authors.forename: John
authors.initials: J
authors.lastname: Conboy
authors.forename: Gargi
authors.initials: G
authors.lastname: Debnath
authors.forename: Amy J
authors.initials: AJ
authors.lastname: Lambert
authors.forename: Luanne L
authors.initials: LL
authors.lastname: Peters
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Baines
authors.forename: Narla
authors.initials: N
authors.lastname: Mohandas
authors.forename: Xiuli
authors.initials: X
authors.lastname: An
mesh_terms: D000818:Animals; D002448:Cell Adhesion; D015815:Cell Adhesion Molecules / Q000378:metabolism*; D015870:Gene Expression; D005854:Germ Cells / Q000378:metabolism*; D015151:Immunoblotting; D007136:Immunoglobulins / Q000378:metabolism*; D007248:Infertility, Male / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008840:Microfilament Proteins / Q000235:genetics / Q000502:physiology*; D016133:Polymerase Chain Reaction; D020033:Protein Isoforms; D012708:Sertoli Cells / Q000166:cytology / Q000378:metabolism*; D013091:Spermatogenesis; D013737:Testis / Q000378:metabolism* / Q000648:ultrastructure
chemical_list: D015815:Cell Adhesion Molecules; C540651:Epb4.1l2 protein, mouse; C498602:Igsf4c protein, mouse; D007136:Immunoglobulins; D008840:Microfilament Proteins; D020033:Protein Isoforms