Genetic Control of MAP3K1 in Eye Development and Sex Differentiation

The MAP3K1 is responsible for transmitting signals to activate specific MAP2K-MAPK cascades. Following the initial biochemical characterization, genetic mouse models have taken center stage to elucidate how MAP3K1 regulates biological functions. To that end, mice were generated with the ablation of the entire Map3k1 gene, the kinase domain coding sequences, or ubiquitin ligase domain mutations. Analyses of the mutants identify diverse roles that MAP3K1 plays in embryonic survival, maturation of T/B cells, and development of sensory organs, including eye and ear. Specifically in eye development, Map3k1 loss-of-function was found to be autosomal recessive for congenital eye abnormalities, but became autosomal dominant in combination with Jnk and RhoA mutations. Additionally, Map3k1 mutation increased eye defects with an exposure to environmental agents such as dioxin. Data from eye developmental models reveal the nexus role of MAP3K1 in integrating genetic and environmental signals to control developmental activities. Here, we focus the discussions on recent advances in understanding the signaling mechanisms of MAP3K1 in eye development in mice and in sex differentiation from human genomics findings. The research works featured here lead to a deeper understanding of the in vivo signaling network, the mechanisms of gene–environment interactions, and the relevance of this multifaceted protein kinase in disease etiology and pathogenesis.

Multiocular organoids from human induced pluripotent stem cells displayed retinal, corneal, and retinal pigment epithelium lineages

Background Recently, great efforts have been made to design protocols for obtaining ocular cells from human stem cells to model diseases or for regenerative purposes. Current protocols generally focus on isolating retinal cells, retinal pigment epithelium (RPE), or corneal cells and fail to recapitulate the complexity of the tissue during eye development. Here, the generation of more advanced in vitro multiocular organoids from human induced pluripotent stem cells (hiPSCs) is demonstrated. Methods A 2-step method was established to first obtain self-organized multizone ocular progenitor cells (mzOPCs) from 2D hiPSC cultures within three weeks. Then, after the cells were manually isolated and grown in suspension, 3D multiocular organoids were generated to model important cellular features of developing eyes. Results In the 2D culture, self-formed mzOPCs spanned the neuroectoderm, surface ectoderm, neural crest, and RPE, mimicking early stages of eye development. After lifting, mzOPCs developed into different 3D multiocular organoids composed of multiple cell lineages including RPE, retina, and cornea, and interactions between the different cell types and regions of the eye system were observed. Within these organoids, the retinal regions exhibited correct layering and contained all major retinal cell subtypes as well as retinal morphological cues, whereas the corneal regions closely resembled the transparent ocular-surface epithelium and contained of corneal, limbal, and conjunctival epithelial cells. The arrangement of RPE cells also formed organoids composed of polarized pigmented epithelial cells at the surface that were completely filled with collagen matrix. Conclusions This approach clearly demonstrated the advantages of the combined 2D-3D construction tissue model as it provided a more ocular native-like cellular environment than that of previous models. In this complex preparations, multiocular organoids may be used to model the crosstalk between different cell types in eye development and disease. Graphical abstract

An Eye in the Replication Stress Response: Lessons From Tissue-Specific Studies in vivo

Several inherited human syndromes that severely affect organogenesis and other developmental processes are caused by mutations in replication stress response (RSR) genes. Although the molecular machinery of RSR is conserved, disease-causing mutations in RSR-genes may have distinct tissue-specific outcomes, indicating that progenitor cells may differ in their responses to RSR inactivation. Therefore, understanding how different cell types respond to replication stress is crucial to uncover the mechanisms of RSR-related human syndromes. Here, we review the ocular manifestations in RSR-related human syndromes and summarize recent findings investigating the mechanisms of RSR during eye development in vivo. We highlight a remarkable heterogeneity of progenitor cells responses to RSR inactivation and discuss its implications for RSR-related human syndromes.

The use of mixed light-emitting diodes and natural light in combination with daylength affects turkey hen performance, eye development, and feather coverage

Lighting is a complex management tool in turkey production, controlled by three parameters; daylength, intensity, and chromaticity. As light-emitting diodes (LED) increase in popularity as alternatives to traditional light sources, research regarding LED impacts on commercial-type turkey production is lacking. Therefore, turkey hens of the same strain were reared under experimental brooding and grow-out conditions with six lighting treatments. An environmentally and light controlled facility (ECF) consisted of 5,000 Kelvin (K) LED or 5,000K + far-red LED (639nm) (RED) with either 12h short or 18h long daylength to test LED spectra. In the remaining treatments, hens were exposed to sunlight in a curtain-sided facility (CSF) as two treatments 1) natural decreasing daylength from September to November (NAT) or 2) natural daylight + 5,000 K LED lighting with an 18h long blocked daylength (BLK). The intensity was 9 footcandles in the ECF and naturally fluctuating in the CSF. Hen's performance was evaluated at 5, 9, and 14 weeks for eye development and feather coverage. Hens brooded and grown-out under NAT light had significantly increased body weight gain compared to BLK hens for the same period. Hens reared with RED LED spectrum had significantly increased eye anterior-posterior distance than birds raised in the NAT treatment. A significant reduction in red heat signature on the breast tissue in the NAT treatment compared to all other 18h treatments indicated improved feather coverage. However, these same results were not observed during serum thyroid hormone analysis. While turkey hens reared under different lighting programs had similar ending performance, lighting parameters significantly affected bird performance during the growing period, bird's eye development, and body feather coverage. Therefore, potential effects on growth patterns and physiology should be considered when choosing a LED lighting program for turkeys