Progenitor cells of the rod-free area centralis originate in the anterior dorsal optic vesicle

<p>Abstract</p> <p>Background</p> <p>Nervous system development is dependent on early regional specification to create functionally distinct tissues within an initially undifferentiated zone. Within the retina, photoreceptors are topographically organized with rod free area centrales faithfully generated at the centre of gaze. How does the developing eye regulate this placement? Conventional wisdom indicates that the distal tip of the growing optic vesicle (OV) gives rise to the area centralis/fovea. Ectopic expression and ablation studies do not fully support this view, creating a controversy as to the origin of this region. In this study, the lineage of cells in the chicken OV was traced using DiI. The location of labelled cells was mapped onto the retina in relation to the rod-free zone at embryonic (E) 7 and E17.5. The ability to regenerate a rod free area after OV ablation was determined in conjunction with lineage tracing.</p> <p>Results</p> <p>Anterior OV gave rise to cells in nasal retina and posterior OV became temporal retina. The OV distal tip gave rise to cells above the optic nerve head. A dorsal and anterior region of the OV correlated with cells in the developing rod free area centralis. Only ablations including the dorsal anterior region gave rise to a retina lacking a rod free zone. DiI application after ablation indicated that cells movements were greater along the anterior/posterior axis compared with the dorsal/ventral axis.</p> <p>Conclusion</p> <p>Our data support the idea that the chicken rod free area centralis originates from cells located near, but not at the distal tip of the developing OV. Therefore, the hypothesis that the area centralis is derived from cells at the distal tip of the OV is not supported; rather, a region anterior and dorsal to the distal tip gives rise to the rod free region. When compared with other studies of retinal development, our results are supported on molecular, morphological and functional levels. Our data will lead to a better understanding of the mechanisms underlying the topographic organization of the retina, the origin of the rod free zone, and the general issue of compartmentalization of neural tissue before any indication of morphological differentiation.</p

Dynamic Coupling of Pattern Formation and Morphogenesis in the Developing Vertebrate Retina

In this Research Article, Picker et al. show how cells in the retina get their spatial coordinates

EphA3 Expressed in the Chicken Tectum Stimulates Nasal Retinal Ganglion Cell Axon Growth and Is Required for Retinotectal Topographic Map Formation

BACKGROUND: Retinotopic projection onto the tectum/colliculus constitutes the most studied model of topographic mapping and Eph receptors and their ligands, the ephrins, are the best characterized molecular system involved in this process. Ephrin-As, expressed in an increasing rostro-caudal gradient in the tectum/colliculus, repel temporal retinal ganglion cell (RGC) axons from the caudal tectum and inhibit their branching posterior to their termination zones. However, there are conflicting data regarding the nature of the second force that guides nasal axons to invade and branch only in the caudal tectum/colliculus. The predominant model postulates that this second force is produced by a decreasing rostro-caudal gradient of EphA7 which repels nasal optic fibers and prevents their branching in the rostral tectum/colliculus. However, as optic fibers invade the tectum/colliculus growing throughout this gradient, this model cannot explain how the axons grow throughout this repellent molecule. METHODOLOGY/PRINCIPAL FINDINGS: By using chicken retinal cultures we showed that EphA3 ectodomain stimulates nasal RGC axon growth in a concentration dependent way. Moreover, we showed that nasal axons choose growing on EphA3-expressing cells and that EphA3 diminishes the density of interstitial filopodia in nasal RGC axons. Accordingly, in vivo EphA3 ectodomain misexpression directs nasal optic fibers toward the caudal tectum preventing their branching in the rostral tectum. CONCLUSIONS: We demonstrated in vitro and in vivo that EphA3 ectodomain (which is expressed in a decreasing rostro-caudal gradient in the tectum) is necessary for topographic mapping by stimulating the nasal axon growth toward the caudal tectum and inhibiting their branching in the rostral tectum. Furthermore, the ability of EphA3 of stimulating axon growth allows understanding how optic fibers invade the tectum growing throughout this molecular gradient. Therefore, opposing tectal gradients of repellent ephrin-As and of axon growth stimulating EphA3 complement each other to map optic fibers along the rostro-caudal tectal axis

Vav2 pharmaco-mimetic mice reveal the therapeutic value and caveats of the catalytic inactivation of a Rho exchange factor

The current paradigm holds that the inhibition of Rho guanosine nucleotide exchange factors (GEFs), the enzymes that stimulate Rho GTPases, can be a valuable therapeutic strategy to treat Rho-dependent tumors. However, formal validation of this idea using in vivo models is still missing. In this context, it is worth remembering that many Rho GEFs can mediate both catalysis-dependent and independent responses, thus raising the possibility that the inhibition of their catalytic activities might not be sufficient per se to block tumorigenic processes. On the other hand, the inhibition of these enzymes can trigger collateral side effects that could preclude the practical implementation of anti-GEF therapies. To address those issues, we have generated mouse models to mimic the effect of the systemic application of an inhibitor for the catalytic activity of the Rho GEF Vav2 at the organismal level. Our results indicate that lowering the catalytic activity of Vav2 below specific thresholds is sufficient to block skin tumor initiation, promotion, and progression. They also reveal that the negative side effects typically induced by the loss of Vav2 can be bypassed depending on the overall level of Vav2 inhibition achieved in vivo. These data underscore the pros and cons of anti-Rho GEF therapies for cancer treatment. They also support the idea that Vav2 could represent a viable drug target.XRB is supported by grants from Worldwide Cancer Research (14-1248), the Castilla-León Government (CSI252P18, CLC-2017-01), the Spanish Ministry of Science and Innovation (MSI) (RTI2018-096481-B-I00), and the Spanish Association against Cancer (GC16173472GARC). XRB’s institution is supported by the Programa de Apoyo a Planes Estratégicos de Investigación de Estructuras de Investigación de Excelencia of the Castilla-León autonomous government (CLC-2017-01). SF, SR-F, and LFL-M contracts have been supported by funding from the MSI (SF, BES-2010-031386; SR-F, BES-2013-063573), the Spanish Ministry of Universities (LFL-M, FPU13/02923), and the CLC-2017-01 grant (SR-F and LFL-M). JR-V has been supported by the CIBERONC and, currently, by the Spanish Association against Cancer. Both Spanish and Castilla-León government-associated funding is partially supported by the European Regional Development Fund.Peer reviewe