The extracellular matrix protein fibronectin promotes metanephric kidney development.

Complex interactions of the branching ureteric bud (UB) and surrounding mesenchymal cells during metanephric kidney development determine the final number of nephrons. Impaired nephron endowment predisposes to arterial hypertension and chronic kidney disease. In the kidney, extracellular matrix (ECM) proteins are usually regarded as acellular scaffolds or as the common histological end-point of chronic kidney diseases.

Induced Attenuation of Scleral TGF-β Signaling in Mutant Mice Increases Susceptibility to IOP-Induced Optic Nerve Damage.

Purpose: Axonal optic nerve (ON) damage in glaucoma is characteristically associated with increased amounts of active transforming growth factor-beta 2 (TGF-β2) in the ON head. Here we investigated the functional role of scleral TGF-β signaling in glaucoma.

Methods: A deficiency of Tgfbr2, which encodes for TGF-β receptor type II (TGF-βRII), the essential receptor for canonical TGF-β signaling, was induced in fibroblasts (including those of the sclera) of mutant mice.

Histomorphometry of the Sural Nerve for Use as a CFNG in Facial Reanimation Procedures.

Facial palsy (FP) is a debilitating nerve pathology. Cross Face Nerve Grafting (CFNG) describes a surgical technique that uses nerve grafts to reanimate the paralyzed face. The sural nerve has been shown to be a reliable nerve graft with little donor side morbidity.

Retinal Pigmented Epithelium-Derived Ectopic Norrin Does Not Promote Intraretinal Angiogenesis in Transgenic Mice.

Formation of intraretinal capillaries and inner blood-retinal barrier during development requires norrin, a ligand of the canonical wingless/integrated (Wnt)/β-catenin signaling pathway. Here we addressed the question whether retinal pigmented epithelium (RPE)-derived overexpression of norrin in transgenic mice rescues the vascular phenotype caused by norrin deficiency. To this end, we generated Ndp/Rpe65-Norrin mice and analyzed the activation of β-catenin signaling, the development of intraretinal capillaries, and the expression of blood-retinal barrier marker molecules.

Intravenous injection of cyclosporin A loaded lipid nanocapsules fights inflammation and immune system activation in a mouse model of diabetic retinopathy.

Inflammation and immune system activation are key pathologic events in the onset and escalation of diabetic retinopathy (DR). Both are driven by cytokines and complement originating from the retinal pigment epithelium (RPE). Despite the RPE's pivotal role, there is no therapeutic tool to specifically interfere with the RPE-related pathomechanism.

A single intravenous injection of cyclosporin A-loaded lipid nanocapsules prevents retinopathy of prematurity.

Retinopathy of prematurity (ROP) is a retinal disease that threatens the vision of prematurely born infants. Severe visual impairment up to complete blindness is caused by neovascularization and inflammation, progressively destroying the immature retina. ROP primarily affects newborns in middle- and low-income countries with limited access to current standard treatments such as intraocular drug injections and laser- or cryotherapy.

Targeted drug delivery to the retinal pigment epithelium: Untapped therapeutic potential for retinal diseases.

The retinal pigment epithelium (RPE) plays a crucial part in sight-threatening diseases. In this review, we shed light on the pivotal implication of the RPE in age-related macular degeneration, diabetic retinopathy and retinopathy of prematurity; and explain why a paradigm shift toward targeted RPE therapy is needed to efficiently fight these retinal diseases. We provide guidance for the development of RPE-specific nanotherapeutics by giving a comprehensive overview of the possibilities and challenges of drug delivery to the RPE and highlight successful nanotherapeutic approaches targeting the RPE.

Deficiency in Retinal TGFβ Signaling Aggravates Neurodegeneration by Modulating Pro-Apoptotic and MAP Kinase Pathways.

Transforming growth factor β (TGFβ) signaling has manifold functions such as regulation of cell growth, differentiation, migration, and apoptosis. Moreover, there is increasing evidence that it also acts in a neuroprotective manner. We recently showed that TGFβ receptor type 2 () is upregulated in retinal neurons and Müller cells during retinal degeneration.

Role of the Pbrm1 subunit and the PBAF complex in Schwann cell development.

Myelin sheath formation in the peripheral nervous system and the ensuing saltatory conduction rely on differentiated Schwann cells. We have previously shown that transition of Schwann cells from an immature into a differentiated state requires Brg1 that serves as the central energy generating subunit in two related SWI/SNF-type chromatin remodelers, the BAF and the PBAF complex. Here we used conditional deletion of Pbrm1 to selectively interfere with the PBAF complex in Schwann cells.

Transcription factor Zfp276 drives oligodendroglial differentiation and myelination by switching off the progenitor cell program.

In oligodendrocytes of the vertebrate central nervous system a complex network of transcriptional regulators is required to ensure correct and timely myelination of neuronal axons. Here we identify Zfp276, the only mammalian ZAD-domain containing zinc finger protein, as a transcriptional regulator of oligodendrocyte differentiation and central myelination downstream of Sox10. In the central nervous system, Zfp276 is exclusively expressed in mature oligodendrocytes.

Consensus Recommendation for Mouse Models of Ocular Hypertension to Study Aqueous Humor Outflow and Its Mechanisms.

Due to their similarities in anatomy, physiology, and pharmacology to humans, mice are a valuable model system to study the generation and mechanisms modulating conventional outflow resistance and thus intraocular pressure. In addition, mouse models are critical for understanding the complex nature of conventional outflow homeostasis and dysfunction that results in ocular hypertension. In this review, we describe a set of minimum acceptable standards for developing, characterizing, and utilizing mouse models of open-angle ocular hypertension.

Angiopoietin-1 Mimetic Nanoparticles for Restoring the Function of Endothelial Cells as Potential Therapeutic for Glaucoma.

A root cause for the development and progression of primary open-angle glaucoma might be the loss of the Schlemm's canal (SC) cell function due to an impaired Angiopoietin-1 (Angpt-1)/Tie2 signaling. Current therapeutic options fail to restore the SC cell function. We propose Angpt-1 mimetic nanoparticles (NPs) that are intended to bind in a multivalent manner to the Tie2 receptor for successful receptor activation.

Microanatomy of the Frontal Branch of the Facial Nerve: The Role of Nerve Caliber and Axonal Capacity.

Background: A commonly seen issue in facial palsy patients is brow ptosis caused by paralysis of the frontalis muscle powered by the frontal branch of the facial nerve. Predominantly, static methods are used for correction. Functional restoration concepts include the transfer of the deep temporal branch of the trigeminal nerve and cross-facial nerve grafts.

SoxD transcription factor deficiency in Schwann cells delays myelination in the developing peripheral nervous system.

The three SoxD proteins, Sox5, Sox6 and Sox13, represent closely related transcription factors with important roles during development. In the developing nervous system, SoxD proteins have so far been primarily studied in oligodendroglial cells and in interneurons of brain and spinal cord. In oligodendroglial cells, Sox5 and Sox6 jointly maintain the precursor state, interfere with terminal differentiation, and thereby ensure the proper timing of myelination in the central nervous system.

Transcriptional Profiling Identifies Upregulation of Neuroprotective Pathways in Retinitis Pigmentosa.

Hereditary retinal degenerations like retinitis pigmentosa (RP) are among the leading causes of blindness in younger patients. To enable in vivo investigation of cellular and molecular mechanisms responsible for photoreceptor cell death and to allow testing of therapeutic strategies that could prevent retinal degeneration, animal models have been created. In this study, we deeply characterized the transcriptional profile of mice carrying the transgene rhodopsin V20G/P23H/P27L (VPP), which is a model for autosomal dominant RP.

A novel ocular function for decorin in the aqueous humor outflow.

Primary open-angle glaucoma, a neurodegenerative disorder characterized by degeneration of optic nerve axons, is a frequent cause of vision loss and blindness worldwide. Several randomized multicenter studies have identified intraocular pressure as the major risk factor for its development, caused by an increased outflow resistance to the aqueous humor within the trabecular meshwork. However, the molecular mechanism for increased outflow resistance in POAG has not been fully established.

CCN2/CTGF promotor activity in the developing and adult mouse eye.

CCN2/CTGF is a matricellular protein that is known to enhance transforming growth factor-β signaling and to induce a myofibroblast-like phenotype in a variety of cell types. Here, we investigated Ccn2/Ctgf promotor activity during development and in the adult mouse eye, using CTGF mice in which the β-galactosidase reporter gene LacZ had been inserted into the open reading frame of Ccn2/Ctgf. Promotor activity was assessed by staining for β-galactosidase activity and by immunolabeling using antibodies against β-galactosidase.

Egr2-guided histone H2B monoubiquitination is required for peripheral nervous system myelination.

Schwann cells are the nerve ensheathing cells of the peripheral nervous system. Absence, loss and malfunction of Schwann cells or their myelin sheaths lead to peripheral neuropathies such as Charcot-Marie-Tooth disease in humans. During Schwann cell development and myelination chromatin is dramatically modified.

Design of dye and superparamagnetic iron oxide nanoparticle loaded lipid nanocapsules with dual detectability in vitro and in vivo.

Lipid nanocapsules are treasured nanoparticulate systems, although they lack detectability in biological environments. To overcome this, we designed LNCs loaded simultaneously with fluorescent dye and superparamagnetic iron oxide nanoparticles (Dual LNCs). The introduction of both labels did not alter nanoparticle characteristics such as size (50 nm), size distribution (polydispersity index < 0.

Endogenous Wnt/β-catenin signaling in Müller cells protects retinal ganglion cells from excitotoxic damage.

Purpose: To analyze whether activation of endogenous wingless (Wnt)/β-catenin signaling in Müller cells is involved in protection of retinal ganglion cells (RGCs) following excitotoxic damage.

Methods: Transgenic mice with a tamoxifen-dependent β-catenin deficiency in Müller cells were injected with N-methyl-D-aspartate (NMDA) into the vitreous cavity of one eye to induce excitotoxic damage of the RGCs, while the contralateral eye received PBS only. Retinal damage was quantified by counting the total number of RGC axons in cross sections of optic nerves and measuring the thickness of the retinal layers on meridional sections.

Norrin Protects Retinal Ganglion Cells from Excitotoxic Damage via the Induction of Leukemia Inhibitory Factor.

Purpose: To investigate whether and how leukemia inhibitory factor (Lif) is involved in mediating the neuroprotective effects of Norrin on retinal ganglion cells (RGC) following excitotoxic damage. Norrin is a secreted protein that protects RGC from methyl-d-aspartate (NMDA)-mediated excitotoxic damage, which is accompanied by increased expression of protective factors such as Lif, Edn2 and Fgf2.

Methods: Lif-deficient mice were injected with NMDA in one eye and NMDA plus Norrin into the other eye.

Increased stiffness and flow resistance of the inner wall of Schlemm's canal in glaucomatous human eyes.

The cause of the elevated outflow resistance and consequent ocular hypertension characteristic of glaucoma is unknown. To investigate possible causes for this flow resistance, we used atomic force microscopy (AFM) with 10-µm spherical tips to probe the stiffness of the inner wall of Schlemm's canal as a function of distance from the tissue surface in normal and glaucomatous postmortem human eyes, and 1-µm spherical AFM tips to probe the region immediately below the tissue surface. To localize flow resistance, perfusion and imaging methods were used to characterize the pressure drop in the immediate vicinity of the inner wall using giant vacuoles that form in Schlemm's canal cells as micropressure sensors.

Significance of the Marginal Mandibular Branch in Relation to Facial Palsy Reconstruction: Assessment of Microanatomy and Macroanatomy Including Axonal Load in 96 Facial Halves.

Background: The marginal mandibular branch (MMB) of the facial nerve provides lower lip symmetry apparent during human smile or crying and is mandatory for vocal phonation. In treating facial palsy patients, so far, little attention is directed at the MMB in facial reanimation surgery. However, isolated paralysis may occur congenital, in Bell's palsy or iatrogenic during surgery, prone to its anatomical course.

QEVO - A new digital endoscopic microinspection tool - A cadaveric study and first clinical experiences (case series).

Background: The use of endoscopes in neurosurgery is well established, but the integration of a full high definition signaling, 45° angled endoscopic tool into a digital surgical microscope, is new. We report our first experiences in a cadaveric study and a clinical case series using the new microinspection tool QEVO that serves as a plug-in feature for the recently launched KINEVO 900 digital visualization platform (CARL ZEISS MEDITEC, Oberkochen, Germany). For illustration purposes, we offer video footage.