BackgroundThe retinal vasculature is a capillary network of blood vessels that nourishes the inner retina of most mammals. Developmental abnormalities or microvascular complications in the retinal vasculature result in severe human eye diseases that lead to blindness. To exploit the advantages of zebrafish for genetic, developmental and pharmacological studies of retinal vasculature, we characterised the intraocular vasculature in zebrafish.ResultsWe show a detailed morphological and developmental analysis of the retinal blood supply in zebrafish. Similar to the transient hyaloid vasculature in mammalian embryos, vessels are first found attached to the zebrafish lens at 2.5 days post fertilisation. These vessels progressively lose contact with the lens and by 30 days post fertilisation adhere to the inner limiting membrane of the juvenile retina. Ultrastructure analysis shows these vessels to exhibit distinctive hallmarks of mammalian retinal vasculature. For example, smooth muscle actin-expressing pericytes are ensheathed by the basal lamina of the blood vessel, and vesicle vacuolar organelles (VVO), subcellular mediators of vessel-retinal nourishment, are present. Finally, we identify 9 genes with cell membrane, extracellular matrix and unknown identity that are necessary for zebrafish hyaloid and retinal vasculature development.ConclusionZebrafish have a retinal blood supply with a characteristic developmental and adult morphology. Abnormalities of these intraocular vessels are easily observed, enabling application of genetic and chemical approaches in zebrafish to identify molecular regulators of hyaloid and retinal vasculature in development and disease.

The transcription factor FOXP1 is a master regulator of stem and progenitor cell biology. In diffuse large B-cell lymphoma (DLBCL), copy number amplifications and chromosomal translocations result in overexpression of FOXP1. Increased FOXP1 protein abundance in DLBCL predicts poor prognosis and resistance to therapy. To connect gene overexpression with phenotype, we developed a genome-wide mass spectrometry-coupled gain-of-function genetic screen, revealing that FOXP1 potentiates β-catenin-dependent Wnt signal transduction. Gain-of-function and loss-of-function studies in cell models and zebrafish confirmed that FOXP1 was a general and conserved co-activator of Wnt signaling. In a Wnt-dependent fashion, FOXP1 co-complexed with β-catenin, TCF7L2, and the acetyltransferase CBP, and bound the promoters of Wnt target genes. FOXP1 promoted the acetylation of β-catenin by CBP, and acetylation was required for FOXP1-potentiation of β-catenin-dependent transcription. In DLBCL, we found that FOXP1 promoted sensitivity to Wnt pathway inhibitors and knockdown of FOXP1 or Wnt signaling slowed xenograft tumor growth. These data connect FOXP1 overexpression with β-catenin-dependent signal transduction, and provide a new molecular rationale for Wnt-directed therapy in DLBCL.

Highlights d In vivo chemical screen identifies regulators of osteoblast dedifferentiation d NF-kB signaling is active in mature osteoblasts and inactive during dedifferentiation d NF-kB signaling inhibits osteoblast dedifferentiation cell autonomously d NF-kB acts upstream of retinoic acid signaling

mab21l1 and mab21l2 paralogs have widespread and dynamic expression patterns during vertebrate development. Both genes are expressed in the developing eye, midbrain, neural tube, and branchial arches. Our goal was to identify promoter regions with activity in mab21l2 expression domains. Assays of mab21l2 promoter-EGFP constructs in zebrafish embryos confirm that constructs containing 7.2 or 4.9 kb of mab21l2 promoter region are sufficient to drive expression in known (e.g., tectum, branchial arches) and unexpected domains (e.g., lens and retinal amacrine cells). A comparative analysis identifies complementary and novel expression domains of endogenous mab21l2 (e.g., lens and ventral iridocorneal canal) and mab21l1 (e.g., retinal amacrine and ganglion cells). Interestingly, therefore, despite the absence of conserved non-coding elements, a 4.9-kb mab21l2 promoter is sufficient to recapitulate expression in tissues unique to mab21l1 or mab21l2. Developmental Dynamics 240:745-754,

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