Focal adhesion kinase is a regulator of F-actin dynamics

Abstract

During spermatogenesis, spermatogonia (2n, diploid) undergo a series of mitotic divisions as well as differentiation to become spermatocytes, which enter meiosis I to be followed by meiosis II to form round spermatids (1n, haploid), and then differentiate into spermatozoa (1n, haploid) via spermiogenesis. These events take place in the epithelium of the seminiferous tubule, involving extensive junction restructuring at the Sertoli-Sertoli and Sertoli-germ cell interface to allow the transport of developing germ cells across the epithelium. Although structural aspects of these cell-cell junctions have been studied, the underlying mechanism(s) that governs these events has yet to be explored. Earlier studies have shown that a non-receptor protein tyrosine kinase known as focal adhesion kinase (FAK) is a likely regulator of these events due to the stage-specific and spatiotemporal expression of its various phosphorylated/activated forms at the testis-specific anchoring junctions in the testis, as well as its association with actin regulatory proteins. Recent studies have shown that FAK, in particular its two activated phosphorylated forms p-FAK-Tyr407 and p-FAK-Tyr397, are crucial regulators in modulating junction restructuring at the Sertoli cell-cell interface at the blood-testis barrier (BTB) known as the basal ectoplasmic specialization (basal ES), as well as at the Sertoli-spermatid interface called apical ES during spermiogenesis via its effects on the filamentous (F)-actin organization at the ES. We herein summarize and critically evaluate the current knowledge regarding the physiological significance of FAK in regulating BTB and apical ES dynamics by governing the conversion of actin filaments at the ES from a “bundled” to a “de-bundled/branched” configuration and vice versa. We also provide a molecular model on the role of FAK in regulating these events based on the latest findings in the field.

Regulation of Blood-Testis Barrier (BTB) Dynamics, Role of Actin-, and Microtubule-Based Cytoskeletons

“…In short, the Arp2/3 is a protein complex composed of seven different proteins. Its intrinsic activity is to bind onto the barbed end of an existing actin microfilament, upon activation by N-WASP (neuronal Wiskott-Aldrich syndrome protein), and the N-WASP/Arp2/3 complex rapidly induces branched actin nucleation [54–59] (Fig. 1d).…”

Autophagy is required for ectoplasmic specialization assembly in sertoli cells

“…9,19 The extensive restructuring of basal and apical ES is crucial to spermatogenesis, and recent studies have shown many molecules and signaling pathways participate in ES restructuring. 6,9,11,14,16 However, the precise mechanism remains elusive.…”

“…6,9,14 The continuous transport of developing germ cells across the seminiferous epithelium requires the ES to undergo dynamic restructuring in the epithelial cycle. 2,12,15,16 At the early stage of the epithelial cycle, the disassembly and reassembly of the basal ES-BTB is necessary for the transit of preleptotene spermatocytes across the BTB to enter the apical compartment and prepare for meiosis. 2,16,17 After spermatocytes enter the apical compartment, the apical ES replaces the desmosome-like junctions and gap junctions in the Sertoligerm cell interface and persists until the spermatids line up at the luminal edge of the seminiferous tubule.…”

Sertoli cell anatomy and cytoskeleton

“…One hypothesis put forward is that biologically active fragments of adhesion-related molecules (γ3-laminin), released or internalized in apical regions in the cell during sperm release, in some way interact with "receptors" at the base of the cell. This then triggers the turnover of basal junction complexes, facilitating spermatocyte translocation [396,399]. The cell biology behind this proposed pathway remains to be elucidated.…”

“…Many elements of these signaling cascades are present in cytoskeletal-containing features of the Sertoli cell that change during spermatogenesis, most notably the actin-containing ectoplasmic specializations. Key among these elements are the kinases ERK [351], Src [202,350], FAK [396], and ILK [275]. The MAP kinase signaling cascade appears particularly significant in the regulation of ectoplasmic specializations and associated junctions [393,397].…”