Animal oviducts and human Fallopian tubes are a part of the female reproductive tract that hosts fertilization and pre-implantation development of the embryo. With an increasing understanding of roles of the oviduct at the cellular and molecular levels, current research signifies the importance of the oviduct on naturally conceived fertilization and pre-implantation embryo development. This review highlights the physiological conditions within the oviduct during fertilization, environmental regulation, oviductal fluid composition and its role in protecting embryos and supplying nutrients. Finally, the review compares different aspects of naturally occurring fertilization and assisted reproductive technology (ART)-achieved fertilization and embryo development, giving insight into potential areas for improvement in this technology.

In the female reproductive tract, the innate immune system is modulated by two sex steroid hormones, estrogen and progesterone. A cyclical wave of neutrophils in the vaginal lumen is triggered by chemokines and correlates with circulating estrogen levels. Classical estrogen signaling in the female reproductive tract is activated through estrogen receptor α (encoded by the Esr1 gene). To study the role of estrogen action in the vagina, we used a mouse model in which Esr1 was conditionally ablated from the epithelial cells (Wnt7a^cre/+; Esr1^f/f). Histological evidence showed that in response to a physical stress, the lack of ESR1 caused the vaginal epithelium to deteriorate due to the absence of a protective cornified layer and a reduction in keratin production. In the absence of ESR1 in the vaginal epithelial tissue, we also observed an excess of neutrophil infiltration, regardless of the estrous cycle stage. The histological presence of neutrophils was found to correlate with persistent enzymatic activity in the cervical-vaginal fluid. Together, these findings suggest that ESR1 activity in the vaginal epithelial cells is required to maintain proper structural integrity of the vagina and immune response, both of which are necessary for protecting the vagina against physical damage and resetting the vaginal environment.

Multiciliated cells of the airways, brain ventricles, and female reproductive tract provide the motive force for mucociliary clearance, cerebrospinal fluid circulation, and ovum transport. Despite their clear importance to human biology and health, the molecular mechanisms underlying multiciliated cell differentiation are poorly understood. Prior studies implicate the distal appendage/transition fiber protein CEP164 as a central regulator of primary ciliogenesis; however, its role in multiciliogenesis remains unknown. In this study, we have generated a novel conditional mouse model that lacks CEP164 in multiciliated tissues and the testis. These mice show a profound loss of airway, ependymal, and oviduct multicilia and develop hydrocephalus and male infertility. Using primary cultures of tracheal multiciliated cells as a model system, we found that CEP164 is critical for multiciliogenesis, at least in part, via its regulation of small vesicle recruitment, ciliary vesicle formation, and basal body docking. In addition, CEP164 is necessary for the proper recruitment of another distal appendage/transition fiber protein Chibby1 (Cby1) and its binding partners FAM92A and FAM92B to the ciliary base in multiciliated cells. In contrast to primary ciliogenesis, CEP164 is dispensable for the recruitment of intraflagellar transport (IFT) components to multicilia. Finally, we provide evidence that CEP164 differentially controls the ciliary targeting of membrane-associated proteins, including the small GTPases Rab8, Rab11, and Arl13b, in multiciliated cells. Altogether, our studies unravel unique requirements for CEP164 in primary versus multiciliogenesis and suggest that CEP164 modulates the selective transport of membrane vesicles and their cargoes into the ciliary compartment in multiciliated cells. Furthermore, our mouse model provides a useful tool to gain physiological insight into diseases associated with defective multicilia. Lining the airways, brain ventricles, and oviducts, multicilia are small hair-like structures that beat in a whip-like motion to propel fluids, such as mucus, over cell surfaces. Dysfunction of multicilia arising from genetic perturbations is most prominently associated with a devastating disorder called primary ciliary dyskinesia (PCD). PCD is a rare genetic disease characterized by hydrocephalus, chronic airway infection, and infertility. Furthermore, defective airway multicilia have been implicated in several respiratory diseases, including cystic fibrosis, asthma, and chronic obstructive pulmonary disorder (COPD). While important to human health, the detailed molecular mechanisms of how multiciliated cells develop remain largely unknown. Here, we establish a new mouse model that lacks the key ciliary protein CEP164 in multiciliated cells. These mice recapitulate many symptoms of PCD patients such as hydrocephalus and infertility. We show that, in the absence of CEP164, differentiation of airway multiciliated cells is severely perturbed at multiple steps. Importantly, our data also suggest that CEP164 differentially regulates the proper recruitment of membrane-associated ciliary proteins. In summary, we have developed a powerful mouse model to study diseases affecting multicilia and shed light on novel roles of CEP164 in multiciliogenesis.

Newly fertilized embryos spend the first few days within the oviduct and are transported to the uterus, where they implant onto the uterine wall. An implantation of the embryo before reaching the uterus could result in ectopic pregnancy and lead to maternal death. Estrogen is necessary for embryo transport in mammals; however, the mechanism involved in estrogen‐mediated cellular function within the oviduct remains unclear. In this study, we show in mouse models that ciliary length and beat frequency of the oviductal epithelial cells are regulated through estrogen receptor α (ESR1) but not estrogen receptor β (ESR2). Gene profiling indicated that transcripts in the WNT/ β‐catenin (WNT/CTNNB1) signaling pathway were regulated by estrogen in mouse oviduct, and inhibition of this pathway in a whole oviduct culture system resulted in a decreased embryo transport distance. However, selective ablation of CTNNB1 from the oviductal ciliated cells did not affect embryo transport, possibly because of a compensatory mechanism via intact CTNNB1 in the adjacent secretory cells. In summary, we demonstrated that disruption of estrogen signaling in oviductal epithelial cells alters ciliary function and impairs embryo transport. Therefore, our findings may provide a better understanding of etiology of the ectopic pregnancy that is associated with alteration of estrogen signals. —Li, S., O'Neill, S. R. S., Zhang, Y., Holtzman, M. J., Takemaru, K.‐I., Korach, K. S., Winuthayanon, W. Estrogen receptor α is required for oviductal transport of embryos. FASEB J . 31, 1595–1607 (2017) www.fasebj.org

In this study we develop and use a gain-of-function mouse allele of the Down syndrome cell adhesion molecule (Dscam) to complement loss-of-function models. We assay the role ofDscamin promoting cell death, spacing, and laminar targeting of neurons in the developing mouse retina. We find that ectopic or overexpression ofDscamis sufficient to drive cell death. Gain-of-function studies indicate thatDscamis not sufficient to increase spatial organization, prevent cell-to-cell pairing, or promote active avoidance in the mouse retina, despite the similarity of theDscamloss-of-function phenotype in the mouse retina to phenotypes observed inDrosophilaDscam1 mutants. Both gain- and loss-of-function studies support a role forDscamin targeting neurites; DSCAM is necessary for precise dendrite lamination, and is sufficient to retarget neurites of outer retinal cells after ectopic expression. We further demonstrate that DSCAM guides dendrite targeting in type 2 dopaminergic amacrine cells, by restricting the stratum in which exploring retinal dendrites stabilize, in aDscamdosage-dependent manner. Based on these results we propose a single model to account for the numerousDscamgain- and loss-of-function phenotypes reported in the mouse retina whereby DSCAM eliminates inappropriately placed cells and connections.

The differential adhesion hypothesis of development states that patterning of organisms, organs and tissues is mediated in large part by expression of cell adhesion molecules. The cues provided by cell adhesion molecules are also hypothesized to facilitate specific connectivity within the nervous system. In this study we characterize a novel mouse mutation in the gene Dscam (Down Syndrome Cell Adhesion Molecule). Vertebrate DSCAM is required for normal development of the central nervous system and has been best characterized in the visual system. In the visual system DSCAM is required for regulation of cell number, mosaic formation, laminar specificity, and refinement of retinal-tectal projections. We have identified a novel mutation in Dscam that results in a single amino acid substitution, R1018P, in the extracellular domain of the DSCAM protein. Mice homozygous for the R1018P mutation develop a subset of defects observed in Dscam null mice. In vitro analysis identified defects in DSCAM^R1018P localization to filopodia. We also find that wild type DSCAM protein is constitutively cleaved and shed from transfected cells. This secretion is inhibited by the R1018P mutation. We also characterized a novel splice isoform of Dscam and identified defects in lamination of type 2 and type 6 cone bipolar cells in Dscam mutant mice. The identification and characterization of partial loss of function mutations in genes such as Dscam will be helpful in predicting signs and symptoms that may be observed in human patients with partial loss of DSCAM function.