Zebrafish Dark-Dependent Behavior Requires Phototransduction by the Pineal Gland.

Located dorsally underneath a thin translucent skull in many teleosts, the pineal gland is a photoreceptive organ known as a key element of the circadian clock system. Nevertheless, the presence of additional routes of photoreception presents a challenge in determining its specific roles in regulating photic-related behavior. Here, we show the importance of the pineal gland in mediating a prolonged motor response of zebrafish larvae to sudden darkness, both as a photodetector and as a circadian pacemaker.

Intracellular delivery and deep tissue penetration of nucleoside triphosphates using photocleavable covalently bound dendritic polycations.

Nucleoside triphosphates (NTPs) are essential in various biological processes. Cellular or even organismal controlled delivery of NTPs would be highly desirable, yet and applications are hampered owing to their negative charge leading to cell impermeability. NTP transporters or NTP prodrugs have been developed, but a spatial and temporal control of the release of the investigated molecules remains challenging with these strategies.

Celebrating the centennial of the most famous experiment in embryology: Hilde Mangold, Hans Spemann and the organizer.

This Issue of Cells & Development celebrates the centennial of the Spemann-Mangold organizer experiment. This was the most famous experiment in embryology and its reverberations have greatly influenced developmental biology. This historical issue describes the impact of the discovery and is a prelude to the second volume of this Festschrift, which will consist of the proceedings of the international meeting to be held in Freiburg University, at the place where the organizer was discovered.

Hilde Mangold: Original microscope slides and records of the gastrula organizer experiments.

The discovery of the amphibian gastrula organizer and its publication by Hans Spemann and Hilde Mangold in 1924 is a foundation of experimental embryology, and has shaped our understanding of embryonic induction and pattern formation in vertebrates until today. The original publication is a piece of scientific art, characterized by the meticulous hand drawings by Hilde Mangold, as well as the text that develops mechanistic concepts of modern embryology. While historic microphotographs of specimens got lost, the original microscope slides and Hilde Mangold's laboratory notebook have been secured in embryological collections until today.

Neurog1 and Olig2 integrate patterning and neurogenesis signals in development of zebrafish dopaminergic and glutamatergic dual transmitter neurons.

Dopaminergic neurons develop in distinct neural domains by integrating local patterning and neurogenesis signals. While the proneural proteins Neurog1 and Olig2 have been previously linked to development of dopaminergic neurons, their dependence on local prepatterning and specific contributions to dopaminergic neurogenesis are not well understood. Here, we show that both transcription factors are differentially required for the development of defined dopaminergic glutamatergic subpopulations in the zebrafish posterior tuberculum, which are homologous to A11 dopaminergic neurons in mammals.

The proneural factors Ascl1a and Ascl1b contribute to the terminal differentiation of dopaminergic GABAergic dual transmitter neurons in zebrafish.

The proneural factor Ascl1 is involved in several steps of neurogenesis, from neural progenitor maintenance to initiation of terminal differentiation and neuronal subtype specification. In neural progenitor cells, Ascl1 initiates the cell-cycle exit of progenitors, and contributes to their differentiation into mainly GABAergic neurons. Several catecholaminergic neuron groups in the forebrain of zebrafish use GABA as co-transmitter, but a potential role of the two paralogues Ascl1a and Ascl1b in their neurogenesis is not understood.

C-terminal variants in CDC42 drive type I interferon-dependent autoinflammation in NOCARH syndrome reversible by ruxolitinib.

C-terminal variants in CDC42 encoding cell division control protein 42 homolog underlie neonatal-onset cytopenia, autoinflammation, rash, and hemophagocytic lymphohistiocytosis (NOCARH). Pyrin inflammasome hyperactivation has been shown to contribute to disease pathophysiology. However, mortality of NOCARH patients remains high despite inflammasome-focused treatments.

CRISPR/Cas9-based QF2 knock-in at the () locus reveals novel -expressing neuron populations in the zebrafish mid- and hindbrain.

Catecholaminergic neuron clusters are among the most conserved neuromodulatory systems in vertebrates, yet some clusters show significant evolutionary dynamics. Because of their disease relevance, special attention has been paid to mammalian midbrain dopaminergic systems, which have important functions in motor control, reward, motivation, and cognitive function. In contrast, midbrain dopaminergic neurons in teleosts were thought to be lost secondarily.

A network of Notch-dependent and -independent her genes controls neural stem and progenitor cells in the zebrafish thalamic proliferation zone.

Neural proliferation zones mediate brain growth and employ Delta/Notch signaling and HES/Her transcription factors to balance neural stem cell (NSC) maintenance with the generation of progenitors and neurons. We investigated Notch-dependency and function of her genes in the thalamic proliferation zone of zebrafish larvae. Nine Notch-dependent genes, her2, her4.

Rhabdomyosarcoma xenotransplants in zebrafish embryos.

Rhabdomyosarcomas (RMS) are the most common pediatric soft tissue sarcomas. High-risk and metastatic disease continues to be associated with very poor prognosis. RMS model systems that faithfully recapitulate the human disease and provide rapid, cost-efficient estimates of antitumor efficacy of candidate drugs are needed to facilitate drug development and personalized medicine approaches.

Genetic ablation of the Bsx homeodomain transcription factor in zebrafish: Impact on mature pineal gland morphology and circadian behavior.

The pineal gland is a neuroendocrine structure in the brain, which produces and secretes the hormone melatonin at nighttime and is considered a key element in the circadian clock system. Early morphogenesis of the gland is controlled by a number of transcription factors, some of which remain active in adult life. One of these is the brain-specific homeobox (Bsx), a highly conserved homeodomain transcription factor with a developmental role in the pineal gland of several species, including zebrafish, and regulatory roles in mature pinealocytes of the rat.

Wnt/β-catenin signaling promotes neurogenesis in the diencephalospinal dopaminergic system of embryonic zebrafish.

Wnt/β-catenin signaling contributes to patterning, proliferation, and differentiation throughout vertebrate neural development. Wnt/β-catenin signaling is important for mammalian midbrain dopaminergic neurogenesis, while little is known about its role in ventral forebrain dopaminergic development. Here, we focus on the A11-like, Otp-dependent diencephalospinal dopaminergic system in zebrafish.

Functional assessment of two variants of unknown significance in TEK by endothelium-specific expression in zebrafish embryos.

Vascular malformations are most often caused by somatic mutations of the PI3K/mTOR and the RAS signaling pathways, which can be identified in the affected tissue. Venous malformations (VMs) commonly harbor PIK3CA and TEK mutations, whereas arteriovenous malformations (AVMs) are usually caused by BRAF, RAS or MAP2K1 mutations. Correct identification of the underlying mutation is of increasing importance, since targeted treatments are becoming more and more relevant, especially in patients with extensive vascular malformations.

Bsx Is Essential for Differentiation of Multiple Neuromodulatory Cell Populations in the Secondary Prosencephalon.

The hypothalamus is characterized by great neuronal diversity, with many neuropeptides and other neuromodulators being expressed within its multiple anatomical domains. The regulatory networks directing hypothalamic development have been studied in detail, but, for many neuron types, control of differentiation is still not understood. The highly conserved Brain-specific homeobox (Bsx) transcription factor has previously been described in regulating and expression in the hypothalamic arcuate nucleus (ARC) in mice.

Chemical Genetics Screen Identifies Epigenetic Mechanisms Involved in Dopaminergic and Noradrenergic Neurogenesis in Zebrafish.

The cell type diversity and complexity of the nervous system is generated by a network of signaling events, transcription factors, and epigenetic regulators. Signaling and transcriptional control have been easily amenable to forward genetic screens in model organisms like zebrafish. In contrast, epigenetic mechanisms have been somewhat elusive in genetic screens, likely caused by broad action in multiple developmental pathways that masks specific phenotypes, but also by genetic redundancies of epigenetic factors.

Conserved Genoarchitecture of the Basal Hypothalamus in Zebrafish Embryos.

Analyses of genoarchitecture recently stimulated substantial revisions of anatomical models for the developing hypothalamus in mammalian and other vertebrate systems. The prosomeric model proposes the hypothalamus to be derived from the secondary prosencephalon, and to consist of alar and basal regions. The basal hypothalamus can further be subdivided into tuberal and mamillary regions, each with distinct subregions.

Developmental Biology: Reissner's Fiber and Straightening of the Body Axis.

A straight longitudinal body axis supports efficient directed locomotion of fish and other vertebrates. New research demonstrates that Reissner's fiber, an enigmatic structure within the spinal central canal, is essential for development of an extended trunk to tail axis.

Bsx controls pineal complex development.

Neuroendocrine cells in the pineal gland release melatonin during the night and, in teleosts, are directly photoreceptive. During development of the pineal complex, a small number of cells migrate leftward away from the pineal anlage to form the parapineal cell cluster, a process that is crucial for asymmetrical development of the bilateral habenular nuclei. Here, we show that, throughout zebrafish embryonic development, the () gene is expressed in all cell types of the pineal complex.

Protection from UV light is an evolutionarily conserved feature of the haematopoietic niche.

Haematopoietic stem and progenitor cells (HSPCs) require a specific microenvironment, the haematopoietic niche, which regulates HSPC behaviour. The location of this niche varies across species, but the evolutionary pressures that drive HSPCs to different microenvironments remain unknown. The niche is located in the bone marrow in adult mammals, whereas it is found in other locations in non-mammalian vertebrates, for example, in the kidney marrow in teleost fish.

Projections of the Diencephalospinal Dopaminergic System to Peripheral Sense Organs in Larval Zebrafish ().

Dopaminergic neurons of the descending diencephalospinal system are located in the posterior tuberculum (PT) in zebrafish (), and correspond in mammals to the A11 group in hypothalamus and thalamus. In the larval zebrafish, they are likely the only source of central dopaminergic projections to the periphery. Here, we characterized posterior tubercular dopaminergic fibers projecting to peripheral sense organs, with a focus on the lateral line neuromasts.

Progesterone modulates microtubule dynamics and epiboly progression during zebrafish gastrulation.

Control of microtubule dynamics is crucial for cell migration. We analyzed regulation of microtubule network dynamics in the zebrafish yolk cell during epiboly, the earliest coordinated gastrulation movement. We labeled microtubules with EMTB-3GFP and EB3-mCherry to visualize and measure microtubule dynamics by TIRF microscopy live imaging.

The Descending Diencephalic Dopamine System Is Tuned to Sensory Stimuli.

The vertebrate diencephalic A11 system provides the sole dopaminergic innervation of hindbrain and spinal cord and has been implicated in modulation of locomotion and sensory processes. However, the exact contributions of sensory stimuli and motor behavior to A11 dopaminergic activity remain unclear. We recorded cellular calcium activity in four anatomically distinct posterior tubercular A11-type dopaminergic subgroups and two adjacent hypothalamic dopaminergic groups in GCaMP7a-transgenic, semi-restrained zebrafish larvae.

An Ultraconserved Brain-Specific Enhancer Within ADGRL3 (LPHN3) Underpins Attention-Deficit/Hyperactivity Disorder Susceptibility.

Background: Genetic factors predispose individuals to attention-deficit/hyperactivity disorder (ADHD). Previous studies have reported linkage and association to ADHD of gene variants within ADGRL3. In this study, we functionally analyzed noncoding variants in this gene as likely pathological contributors.

A Cue for Driving Large-Scale Cell Movement.

The earliest cell movements that initiate gastrulation in the vertebrate embryo have always fascinated embryologists, but signals controlling this large-scale morphogenesis where nearly all cells move have been elusive. Reporting in Developmental Cell, Szabó et al. (2016) uncover a mechanism for morphogenesis based on complement system C3a/C3aR-directed chemotaxis.