Collective cell migration is fundamental for life and a hallmark of cancer. Neural crest (NC) cells migrate collectively, but the mechanisms governing this process remain controversial. Previous analyses in Xenopus indicate that cranial NC (CNC) cells are a homogeneous population relying on cell-cell interactions for directional migration, while chick embryo analyses suggest a heterogeneous population with leader cells instructing directionality. Our data in chick and zebrafish embryos show that CNC cells do not require leader cells for migration and all cells present similar migratory capacities. In contrast, laser ablation of trunk NC (TNC) cells shows that leader cells direct movement and cell-cell contacts are required for migration. Moreover, leader and follower identities are acquired before the initiation of migration and remain fixed thereafter. Thus, two distinct mechanisms establish the directionality of CNC cells and TNC cells. This implies the existence of multiple molecular mechanisms for collective cell migration.

Obesity is strongly linked to genes regulating neuronal signaling and function, implicating the central nervous system in the maintenance of body weight and energy metabolism. Genome-wide association studies identified significant associations between body mass index (BMI) and multiple loci near Cell adhesion molecule2 (CADM2), which encodes a mediator of synaptic signaling enriched in the brain. Here we sought to further understand the role of Cadm2 in the pathogenesis of hyperglycemia and weight gain. We first analyzed Cadm2 expression in the brain of both human subjects and mouse models and subsequently characterized a loss-of-function mouse model of Cadm2 for alterations in glucose and energy homeostasis. We show that the risk variant rs13078960 associates with increased CADM2 expression in the hypothalamus of human subjects. Increased Cadm2 expression in several brain regions of Lepob/ob mice was ameliorated after leptin treatment. Deletion of Cadm2 in obese mice (Cadm2/ob) resulted in reduced adiposity, systemic glucose levels, and improved insulin sensitivity. Cadm2-deficient mice exhibited increased locomotor activity, energy expenditure rate, and core body temperature identifying Cadm2 as a potent regulator of systemic energy homeostasis. Together these data illustrate that reducing Cadm2 expression can reverse several traits associated with the metabolic syndrome including obesity, insulin resistance, and impaired glucose homeostasis.

Coordination of cell proliferation and migration is fundamental for life, and its dysregulation has catastrophic consequences, such as cancer. How cell cycle progression affects migration, and vice versa, remains largely unknown. We address these questions by combining in silico modelling and in vivo experimentation in the zebrafish trunk neural crest (TNC). TNC migrate collectively, forming chains with a leader cell directing the movement of trailing followers. We show that the acquisition of migratory identity is autonomously controlled by Notch signalling in TNC. High Notch activity defines leaders, while low Notch determines followers. Moreover, cell cycle progression is required for TNC migration and is regulated by Notch. Cells with low Notch activity stay longer in G₁ and become followers, while leaders with high Notch activity quickly undergo G₁/S transition and remain in S-phase longer. In conclusion, TNC migratory identities are defined through the interaction of Notch signalling and cell cycle progression.

Purpose: The zebrafish (Danio rerio) has become an important animal model in a wide range of biomedical research disciplines. Growing awareness of the role of biomechanical properties in tumor progression and neuronal development has led to an increasing interest in the noninvasive mapping of the viscoelastic properties of zebrafish by elastography methods applicable to bulky and nontranslucent tissues.Methods: Microscopic multifrequency MR elastography is introduced for mapping shear wave speed (SWS) and loss angle (φ) as markers of stiffness and viscosity of muscle, brain, and neuroblastoma tumors in postmortem zebrafish with 60 µm in‐plane resolution. Experiments were performed in a 7 Tesla MR scanner at 1, 1.2, and 1.4 kHz driving frequencies.Results: Detailed zebrafish viscoelasticity maps revealed that the midbrain region (SWS = 3.1 ± 0.7 m/s,φ = 1.2 ± 0.3 radian [rad]) was stiffer and less viscous than telencephalon (SWS = 2.6 ± 0. 5 m/s,φ = 1.4 ± 0.2 rad) and optic tectum (SWS = 2.6 ± 0.5 m/s,φ = 1.3 ± 0.4 rad), whereas the cerebellum (SWS = 2.9 ± 0.6 m/s,φ = 0.9 ± 0.4 rad) was stiffer but less viscous than both (allp < .05). Overall, brain tissue (SWS = 2.9 ± 0.4 m/s,φ = 1.2 ± 0.2 rad) had similar stiffness but lower viscosity values than muscle tissue (SWS = 2.9 ± 0.5 m/s,φ = 1.4 ± 0.2 rad), whereas neuroblastoma (SWS = 2.4 ± 0.3 m/s,φ = 0.7 ± 0.1 rad, allp < .05) was the softest and least viscous tissue.Conclusion: Microscopic multifrequency MR elastography‐generated maps of zebrafish show many details of viscoelasticity and resolve tissue regions, of great interest in neuromechanical and oncological research and for which our study provides first reference values.

Only half of patients with relapsed B-cell precursor (BCP) acute lymphoblastic leukemia (ALL) currently survive with standard treatment protocols. Predicting individual patient responses to defined drugs prior to application would help therapy stratification and could improve survival. With the purpose to aid personalized targeted treatment approaches, we developed a human–zebrafish xenograft (ALL-ZeFiX) assay to predict drug response in a patient in 5 days. Leukemia blast cells were pericardially engrafted into transiently immunosuppressed Danio rerio embryos, and engrafted embryos treated for the test case, venetoclax, before single-cell dissolution for quantitative whole blast cell analysis. Bone marrow blasts from patients with newly diagnosed or relapsed BCP-ALL were successfully expanded in 60% of transplants in immunosuppressed zebrafish embryos. The response of BCP-ALL cell lines to venetoclax in ALL-ZeFiX assays mirrored responses in 2D cultures. Venetoclax produced varied responses in patient-derived BCP-ALL grafts, including two results mirroring treatment responses in two refractory BCP-ALL patients treated with venetoclax. Here we demonstrate proof-of-concept for our 5-day ALL-ZeFiX assay with primary patient blasts and the test case, venetoclax, which after expanded testing for further targeted drugs could support personalized treatment decisions within the clinical time window for decision-making.

Juan Lazaro-Navarro, Helia Judith Pimentel-Gutiérrez, Anton Gauert, Anja I.H. Hagemann, Jassi Lena Eisenschmid, Nicola Goekbuget, Binje Vick, Irmela Jeremias, F