Birthdate and Outgrowth Timing Predict Cellular Mechanisms of Axon Target Matching in the Developing Visual Pathway

Abstract

Summary How axons select their appropriate targets in the brain remains poorly understood. Here we explored the cellular mechanisms of axon-target matching in the developing visual system by comparing four transgenic mouse lines, each with a different population of genetically labeled retinal ganglion cells (RGCs) that connect to unique combinations of brain targets. We discovered that the time when an RGC axon arrives in the brain is correlated with its target selection strategy. Early-born, early-arriving RGC axons initially innervate multiple targets. Subsequently, most of those connections were removed. By contrast, later born, later-arriving RGC axons were highly accurate in their initial target choices. These data reveal the diversity of cellular mechanisms axons use to pick their targets and they highlight the key role of birthdate and outgrowth timing for influencing this precision. Timing-based mechanisms may underlie the assembly of the other sensory pathways and complex neural circuitry in the brain.

Functional Assembly of Accessory Optic System Circuitry Critical for Compensatory Eye Movements

“…Although there is residual innervation of the dorsal-most and ventral-most regions of the MTN, axon projections to most of the MTN are absent in Sema6A −/− mutants (n=13 animals, phenotype observed with complete penetrance and expressivity). To further investigate On DSGC-MTN innervation we used two mouse lines that genetically label On DSGCs: SPIG1::GFP , which labels a subset of MTN-innervating On DSGCs from embryonic stage e12.5 to postnatal developmental stages up to ~P13 (Yonehara et al, 2009; Yonehara et al, 2008), when the GFP signal becomes very weak; and Hoxd10-GFP , which labels all On DSGCs from late embryonic stages through adulthood (Dhande et al, 2013; Osterhout et al, 2014). We observed GFP expression following introduction of these GFP alleles into Sema6A −/− mutants and found that both SPIG1::GFP + (Figures 2C–D’) and Hoxd10-GFP + (Figures S2A–B’) projections that innervate the MTN are greatly diminished in Sema6A −/− mutants, providing additional support for the conclusion that Sema6A is required for On DSGC connectivity with the MTN.…”

The Ciliary Margin Zone of the Mammalian Retina Generates Retinal Ganglion Cells

“…A displaced neurogenetic wave is observed in the albino ventral retina, where iRGC production is shifted and, as a consequence, fewer ipsilateral and more contralateral RGCs are born (Bhansali et al, 2014). Indeed, the time of neurogenesis can determine neuronal cell fate and circuitry (Imamura et al, 2011, Molyneaux et al, 2007, Osterhout et al, 2014, Tripodi et al, 2011, Elliott et al, 2008, Mattar et al, 2015, Livesey and Cepko, 2001). Our EdU birthdating results are in line with the hypothesis that in the CMZ, CyclinD2 plays a role in cell cycle regulation within this neurogenic niche.…”

Development of Dendritic Form and Function

“…A similar principle operates in the vertebrate retina, where subtypes of RGCs and amacrine cells-identified by their physiological light responses, neurotransmitter phenotypes, or gene expression profiles-have stereotyped dendritic projections to IPL sublayers (Figure 4a) (Famiglietti & Kolb 1976, Siegert et al 2009, Wässle 2004. RGC and amacrine subtype fate choices, including laminar-targeting decisions, are correlated with and likely specified by birthdate (Cherry et al 2009, De la Huerta et al 2012, Osterhout et al 2014, Voinescu et al 2009). A few transcription factors controlling laminar choice have been identified, but none of these alter IPL stratification without changing other aspects of cell fate, such as neurotransmitter type (Cherry et al 2011, Kay et al 2011.…”