DSCAM promotes axon fasciculation and growth in the developing optic pathway

Abstract

Although many aspects of optic pathway development are beginning to be understood, the mechanisms promoting the growth of retinal ganglion cell (RGC) axons toward visual targets remain largely unknown. Down syndrome cell adhesion molecule (Dscam) is expressed by mouse RGCs shortly after they differentiate at embryonic day 12 and is essential for multiple aspects of postnatal visual system development. Here we show that Dscam is also required during embryonic development for the fasciculation and growth of RGC axons. Dscam is expressed along the developing optic pathway in a pattern consistent with a role in regulating RGC axon outgrowth. In mice carrying spontaneous mutations in Dscam (Dscam), RGC axons pathfind normally, but growth from the chiasm toward their targets is impaired, resulting in a delay in RGC axons reaching the dorsal thalamus compared with that seen in wild-type littermates. Conversely, Dscam gain of function results in exuberant growth into the dorsal thalamus. The growth of ipsilaterally projecting axons is particularly affected. Axon organization in the optic chiasm and tract and RGC growth cone morphologies are also altered in Dscam mutants. In vitro DSCAM promotes RGC axon growth and fasciculation, and can act independently of cell contact. In vitro and in situ DSCAM is required both in the RGC axons and in their environment for the promotion of axon outgrowth, consistent with a homotypic mode of action. These findings identify DSCAM as a permissive signal that promotes the growth and fasciculation of RGC axons, controlling the timing of when RGC axons reach their targets.axon guidance | development | growth cone | optic chiasm | visual system T he developing vertebrate visual system has proven to be one of the most informative model systems for studying axon growth and guidance decision (1). In mice, retinal ganglion cell (RGC) axons grow into the brain from embryonic day (E) 12.5, although mapping within visual targets is not complete until postnatal stages (1). Molecules have been identified that are important for multiple aspects of RGC axon growth and pathfinding, including guidance out of the eye, constraining the general path followed by RGC axons and midline routing at the optic chiasm underlying the establishment of stereovision (1); however, the majority of these molecules induce inhibitory responses in RGC axons. Much less is known about the growth-promoting mechanisms that drive RGC axon extension.Down syndrome cell adhesion molecule 1 (Dscam1) is a homophilic adhesion molecule essential for multiple aspects of neural circuit formation in Drosophila, including axon growth, fasciculation, and pathfinding; dendritic field organization; and synaptic specificity and targeting (2, 3). Although vertebrate Dscam lacks the extensive alternative splicing of fly Dscam1, it is required for many of the same developmental processes, including dendritic arborization and synaptic lamination and refinement (4).Dscam is expressed by mouse RGCs from E12.5 (5) and, through regulation of cell deat...

Dscamgene triplication causes neocortical overinhibition in Down syndrome

“…An important question is whether Dscam functions cell-autonomously to promote presynaptic growth in GABAergic neurons. Previous studies in Drosophila sensory neurons and gain-offunction studies in mouse retinal ganglion cells suggest a cell-autonomous role of Dscam in promoting axonal growth (11,22). Genetic deletion of Dscam in single ChCs is challenging because the Cre activity in Nkx2.1-CreER mouse line is weak.…”

“…In fact, altered Dscam expression levels have been reported in multiple brain disorders, including Down syndrome (DS) (14), autism spectrum disorders (ASD) (15)(16)(17), intractable epilepsy (18), bipolar disorder (19), and possibly Fragile X syndrome (11,12,20,21). Although recent findings suggest a conserved role of Dscam in promoting presynaptic growth in vertebrates (22,23), whether dysregulated Dscam expression results in neuronal defects in brain disorders remains unknown.…”

Separate transcriptionally regulated pathways specify distinct classes of sister dendrites in a nociceptive neuron

“…EGL-44/EGL-46 targets likely include downstream effectors that mediate fasciculation of PVD 2° dendrites with motor neuron commissures. Multiple cell surface proteins including Dscam (Bruce et al, 2017), members of the L1CAM family and receptor tyrosine kinases and phosphatases (Feng et al, 2013; Van Vactor, 1998; Wu et al, 2001) as well as secreted Ig domain proteins (Aurelio et al, 2002) have been shown to mediate inter-axonal fasciculation, but much less is known of the factors that direct dendritic bundling (Barry et al, 2010). Our observation that the mec-3 PVD branching defect is more severe than that of double mutants in which both hpo-30 and egl-44 are inactivated suggests that dendrite morphogenesis also depends on other mec-3 -regulated components.…”

Cranial Pair II: The Optic Nerves

“…Once they pass the optic chiasm region RGC axons continue navigating to enter the optic tracts and reach the visual targets guided by other guidance molecules. The Down syndrome cell adhesion molecule ( Dscam ) seems to be important for axonal fasciculation at this level of the pathway (Bruce et al ., ). However, molecules and mechanisms guiding RGC axons once they trespass the optic chiasm, are out of the scope of this review and we will not discuss them further.…”