Retinal Ganglion Cell Axon Sorting at the Optic Chiasm Requires Dystroglycan

Abstract

Statement 1Abnormal retinal ganglion cell axon sorting in the optic chiasm in the absence of 2 functional dystroglycan results in profound defects in retinorecipient innervation. 3 4 Abstract 5In the developing visual system, retinal ganglion cell (RGC) axons project 6 from the retina to several distal retinorecipient regions in the brain. Several 7 molecules have been implicated in guiding RGC axons in vivo, but the role of 8 extracellular matrix molecules in this process remains poorly understood. 9Dystroglycan is a laminin-binding transmembrane protein important for formation 10 and maintenance of the extracellular matrix and basement membranes and has 11 previously been implicated in axon guidance in the developing spinal cord. Using 12 two genetic models of functional dystroglycan loss, we show that dystroglycan is 13 necessary for correct sorting of contralateral and ipsilateral RGC axons at the 14 optic chiasm. Missorted axons still target retinorecipient brain regions and persist 15 in adult mice, even after axon pruning is complete. Our results highlight the 16 importance of the extracellular matrix for axon sorting at an intermediate choice 17 point in the developing visual circuit. 18 19

Slit2 is necessary for optic axon organization in the zebrafish ventral midline

“…Axon sorting at the optic chiasm has been extensively studied in mice, where it is important, for example, for ipsilateral projection. Here, dystroglycan depletion resulted in chiasm axon sorting defects (Clements and Wright, 2018), while a similar observation was made for heparan sulfate proteoglycan in the zebrafish (Lee et al, 2004). Since these extracellular matrix molecules are known to bind Slits with high affinity, it has been suggested that the axon sorting alterations occur as a result of a disruption in the extracellular distribution of Slit2 (Wright et al, 2012).…”

A cell-ECM mechanism for connecting the ipsilateral eye to the brain

“…Intrinsic transcriptional codes not only differentiate ipsiRGCs from contraRGCs (2, 25), they also provide these ipsilateral projecting cells with a unique repertoire of cell surface receptors to respond uniquely to molecule cues as they course into the brain. Indeed, cell-cell and cell-ECM mechanisms drive the divergence of ipsiRGC axons at the optic chiasm and their homophilic fasciculation in the optic tract (51, 52, 54, 55).…”

Conversations with Ray Guillery on albinism: linking Siamese cat visual pathway connectivity to mouse retinal development

“…After mingling with each other in the optic chiasm, crossed and uncrossed fibers immediately segregate in the proximal optic tract (Sitko et al ., ). The molecular underpinnings of this segregation are beginning to emerge, and include dystroglycan (Clements & Wright, ), matrix molecules (Reese et al ., , ; Hornberg et al ., ), glial cells (Reese et al ., ; Lee et al ., ), and elements important for local translation of guidance proteins (Hornberg et al ., ), but a strict expression pattern associated with the ipsi‐ vs. contralateral RGC populations has not been established. Our in vitro analyses indicate that mouse ipsilateral RGCs have a greater propensity to fasciculate with their own ‘kind’ compared with contralateral RGCs (Sitko et al ., ).…”