Biology subjects

Zagar, Y.

Publications and source records attributed to Zagar, Y..

3 recordsLinked to original sources

bioRxiv2023

Axon guidance during CNS regeneration is required for specific brain innervation

Reconstruction of functional neuronal circuits in the mature brain remains a big challenge in the field of central nervous system (CNS) repair. Despite achievement of robust, long-distance regeneration through modulation of specific neuronal intrinsic growth properties, functional recovery is still limited due to major guidance defects of regenerating axons. Using co-activation of mTOR, JAK/STAT and c-myc pathways in retinal ganglion cells (RGC), we highlight that regenerating axons avoid the suprachiasmatic nucleus (SCN) due to repulsive mechanisms. We show that Slit/Robo guidance signaling is responsible for this reinnervation failure. In vivo suppression of this repulsive signaling allows regenerating axons to enter the SCN. The newly formed circuit is associated with functional behavioral recovery. Our results provide evidence that axon guidance mechanisms are required in the context of mature neuronal circuit repair.

neuroscience↗

bioRxiv2023

Subcellular second messenger networks drive distinct repellent-induced axon behaviors

AO_SCPLOWBSTRACTC_SCPLOWSecond messengers, including cAMP, cGMP and Ca2+ are often placed in an integrating position to combine the extracellular cues that orient growing axons in the developing brain. This view suggests that axon repellents share the same set of cellular messenger signals and that axon attractants evoke opposite cAMP, cGMP and Ca2+ changes. Investigating the confinement of these second messengers in cellular nanodomains, we instead demonstrate that two repellent cues, ephrin-A5 and Slit1, induce spatially segregated signals. These guidance molecules activate subcellular-specific second messenger crosstalks, each signaling network controlling distinct axonal morphology changes in vitro and pathfinding decisions in vivo.

developmental biology↗

bioRxiv2020

The DCC receptor regulates astroglial development essential for telencephalic morphogenesis and corpus callosum formation

The forebrain hemispheres are predominantly separated during embryogenesis by the interhemispheric fissure (IHF). Radial astroglia remodel the IHF to form a continuous substrate between the hemispheres for midline crossing of the corpus callosum (CC) and hippocampal commissure (HC). DCC and NTN1 are molecules that have an evolutionarily conserved function in commissural axon guidance. The CC and HC are absent in Dcc and Ntn1 knockout mice, while other commissures are only partially affected, suggesting an additional aetiology in forebrain commissure formation. Here, we find that these molecules play a critical role in regulating astroglial development and IHF remodelling during CC and HC formation. Human subjects with DCC mutations display disrupted IHF remodelling associated with CC and HC malformations. Thus, axon guidance molecules such as DCC and NTN1 first regulate the formation of a midline substrate for dorsal commissures prior to their role in regulating axonal growth and guidance across it.

neuroscience↗