Reelin Is Required for Class-Specific Retinogeniculate Targeting

Abstract

Development of visual system circuitry requires the formation of precise synaptic connections between neurons in the retina and brain. For example, retinal ganglion cells (RGCs) form synapses onto neurons within subnuclei of the lateral geniculate nucleus (LGN) – i.e. the dorsal LGN (dLGN), ventral LGN (vLGN) and intergeniculate leaflet (IGL). Distinct classes of RGCs project to these subnuclei: the dLGN is innervated by image-forming RGCs, while the vLGN and IGL are innervated by non-image-forming RGCs. To explore potential mechanisms regulating class-specific LGN targeting we sought to identify differentially expressed targeting molecules in these LGN subnuclei. One candidate targeting molecule enriched in the vLGN and IGL during retinogeniculate circuit formation was the extracellular matrix molecule reelin. Anterograde labeling of RGC axons in mutant mice lacking functional reelin (relnrl/rl) revealed reduced patterns of vLGN and IGL innervation and misrouted RGC axons in adjacent non-retino-recipient thalamic nuclei. Using genetic reporter mice, we further demonstrated that mistargeted axons were from non-image-forming, intrinsically-photosensitive RGCs (ipRGCs). In contrast to mistargeted ipRGC axons, axons arising from image-forming RGCs and layer VI cortical neurons correctly targeted the dLGN in relnrl/rl mutants. Taken together, these data reveal reelin is essential for the targeting of LGN subnuclei by functionally distinct classes of RGCs.

The Retinal Projectome Reveals Brain-Area-Specific Visual Representations Generated by Ganglion Cell Diversity

“…For example, Cadherin-6 function is specifically required for proper innervation of two pretectal nuclei by a heterogeneous population of genetically defined RGCs [40]. It has also been shown that Reelin signaling is required for proper innervation of the vLGN by intrinsically photosensitive RGCs (ipRGCs) [41]. Together, these findings support the existence of genetic programs that ensure RGC-type-specific targeting of each retinorecipient area.…”

Nuclei-specific differences in nerve terminal distribution, morphology, and development in mouse visual thalamus

“…In many brain regions, GAD65 and GAD67 are present in different subsets of inhibitory nerve terminals [38-40]. This appears to be the case in both dLGN and IGL since GAD67 + /GAD65 - terminals were present in dLGN and GAD67 - /GAD65 + terminals were present in IGL (Figure 1A,C-F and [37]). Since terminals in vLGN were labeled with antibodies against both GAD67 and GAD65, it remains unclear whether these terminals co-express both enzymes, or whether these represent two unique populations of inhibitory nerve terminals in vLGN.To confirm differences in inhibitory terminal distribution in dLGN and vLGN, we labeled inhibitory terminals with antibodies against VGAT.…”

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

“…By contrast, Cdh3-RGC axons reached the brain very early and underwent widespread refinement. Type 1 intrinsically photosensitive RGCs (M1 ipRGCs) also innervate their targets postnatally and do not make targeting errors (McNeill et al, 2011; Su et al, 2011). Thus, for five parallel eye-to-brain pathways, time of axon arrival correlates with the frequency of transient target innervation: early arrival correlates with extensive transient targeting, late arrival leads to no transient targeting, and axons that arrive in the interim transiently sample a minimal number of targets (Figure 5J).…”

“…In mice lacking Cdh6, Cdh3-RGCs incorrectly project beyond those targets(Osterhout et al, 2011). In addition, Reelin (which can regulate cadherin expression), is required for accurate ipRGC targeting in the thalamus (Franco et al, 2011; Su et al, 2011). …”