Bioactive isoprenoids guide migrating germ cells to the embryonic gonad

Germ cells are essential to sexual reproduction. Across the animal kingdom, extracellular isoprenoids, such as retinoic acids (RAs) in vertebrates and juvenile hormones (JHs) in insects, impact the germline lifecycle from meiosis to gametogenesis. Emerging evidence suggests that these bioactive isoprenoids also influence embryonic reproductive development, though the precise functions remain unclear. Here, we investigated the specific molecular pathways by which JHs regulates embryonic germ cell development in Drosophila. With a newly generated in vivo reporter, we find that JH signaling is active in the vicinity of germ cells as they migrate to colonize the somatic gonad. Through a combination of in vivo and in vitro assays, we find that JHs are both necessary and sufficient for primordial germ cell migration through mechanisms independent of canonical nuclear receptor-mediated transcription. These findings reveal that JH is present during Drosophila embryogenesis and that bioactive isoprenoids impact germ cell development earlier than previously appreciated. Interestingly, we find that like JH in Drosophila, RA is sufficient for murine germ cell migration in vitro, suggesting that the impact of bioactive isoprenoids on embryonic germ cell development may be broadly conserved.

LIM Homeodomain (LIM-HD) Genes and Their Co-Regulators in Developing Reproductive System and Disorders of Sex Development

LIM homeodomain (LIM-HD) family genes are transcription factors that play crucial roles in a variety of functions during embryonic development. The activities of the LIM-HD proteins are regulated by the co-regulators LIM only (LMO) and LIM domain-binding (LDB). In the mouse genome, there are 13 LIM-HD genes (<i>Lhx1</i>–<i>Lhx9</i>, <i>Isl1</i>–<i>2</i>, <i>Lmx1a</i>–<i>1b</i>), 4 Lmo genes (<i>Lmo1</i>–<i>4</i>), and 2 Ldb genes (<i>Ldb1</i>–<i>2</i>). Amongst these, <i>Lhx1</i> is required for the development of the müllerian duct epithelium and the timing of the primordial germ cell migration. <i>Lhx8</i> is necessary for oocyte differentiation and <i>Lhx9</i> for somatic cell proliferation in the genital ridges and control of testosterone production in the Leydig cells. <i>Lmo4</i> is involved in Sertoli cell differentiation. Mutations in <i>LHX1</i> are associated with müllerian agenesis or Mayer-Rokitansky-Kuster-Hauser (MRKH) syndrome. <i>LHX9</i> gene variants are reported in cases with disorders of sex development (DSD). Mutations in <i>LHX3</i> and <i>LHX4</i> are reported in patients with combined pituitary hormone deficiency having absent or delayed puberty. A transcript map of the <i>Lhx</i>, <i>Lmo,</i> and <i>Ldb</i> genes reveal that multiple LIM-HD genes and their co-regulators are expressed in a sexually dimorphic pattern in the developing mouse gonads. Unraveling the roles of LIM-HD genes during development will aid in our understanding of the causes of DSD.

Zebrafish Primordial Germ Cell Migration

Similar to many other organisms, zebrafish primordial germ cells (PGCs) are specified at a location distinct from that of gonadal somatic cells. Guided by chemotactic cues, PGCs migrate through embryonic tissues toward the region where the gonad develops. In this process, PGCs employ a bleb-driven amoeboid migration mode, characterized by low adhesion and high actomyosin contractility, a strategy used by other migrating cells, such as leukocytes and certain types of cancer cells. The mechanisms underlying the motility and the directed migration of PGCs should be robust to ensure arrival at the target, thereby contributing to the fertility of the organism. These features make PGCs an excellent model for studying guided single-cell migration in vivo. In this review, we present recent findings regarding the establishment and maintenance of cell polarity that are essential for motility and discuss the mechanisms by which cell polarization and directed migration are controlled by chemical and physical cues.

Publisher Correction: Delay in primordial germ cell migration in adamts9 knockout zebrafish

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Delay in primordial germ cell migration in adamts9 knockout zebrafish

Adamts9 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 9) is one of a few metalloproteinases structurally conserved from C. elegans to humans and is indispensable in germ cell migration in invertebrates. However, adamts9′s roles in germ cell migration in vertebrates has not been examined. In the present study, we found zygotic expression of adamts9 started around the germ ring stage and reached peak levels at 3 days post fertilization (dpf) in zebrafish. The migration of primordial germ cells (PGC) was completed within 24 hours (h) in wildtype siblings, while a delay in PGC migration was found at 15 and 24-h post-fertilization (hpf) in the Adamts9 knockout (KO). However, the delayed PGC migration in Adamts9 KO disappeared at 48 hpf. Our study suggests a conserved function of Adamts9 in germ cell migration among invertebrates and vertebrates. In addition, our results also suggest that Adamts9 is not essential for germ cell migration as reported in C. elegans, possibly due to expansion of Adamts family members and compensatory roles from other metalloproteinases in vertebrates. Further studies are required in order to elucidate the functions and mechanisms of metalloproteinases in germ cell migration and gonad formation in vertebrates.

Delay in Primordial Germ Cell Migration in Adamts9 Knockout Zebrafish

Adamts9 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 9) is one of few metalloproteinases structurally conserved from C. elegans to humans and is indispensable in germ cell migration in invertebrates. However, adamts9’s roles in germ cell migration in vertebrates has not been examined. In the present study, we found zygotic expression of adamts9 started around germ ring stage and reached peak levels at 3 days post fertilization (dpf) in zebrafish. Germ cell migration completed within 24 hours in wildtype sibling, while a delay in germ cell migration was found at 15 and 24-hours post-fertilization (hpf) in the Adamts9 knockout (KO). However, this delayed effect of Adamts9 KO disappeared at 48 hpf. Our study suggests a conserved function of Adamts9 in germ cell migration among invertebrates and vertebrates. In addition, our results also suggest that Adamts9 is not essential for germ cell migration as reported in C. elegans, possibly due to expansion of Adamts family members and compensatory roles from another metalloproteinase in vertebrates. Further studies are required in order to elucidate the functions and mechanisms of metalloproteinases in germ cell migration and gonad formation in vertebrates.

Seeing around corners: Cells solve mazes and respond at a distance using attractant breakdown

During development and metastasis, cells migrate large distances through complex environments. Migration is often guided by chemotaxis, but simple chemoattractant gradients between a source and sink cannot direct cells over such ranges. We describe how self-generated gradients, created by cells locally degrading attractant, allow single cells to navigate long, tortuous paths and make accurate choices between live channels and dead ends. This allows cells to solve complex mazes efficiently. Cells’ accuracy at finding live channels was determined by attractant diffusivity, cell speed, and path complexity. Manipulating these parameters directed cells in mathematically predictable ways; specific combinations can even actively misdirect them. We propose that the length and complexity of many long-range migratory processes, including inflammation and germ cell migration, means that self-generated gradients are needed for successful navigation.