The decussation of the retinal ganglion cell (RGC) projections in the optic chiasm is essential for normal mapping of visual information, and insures that each hemisphere receives information from both eyes to establish binocular vision. How the development of the binocular pathway is determined has been a longstanding enigma. Recent work in the spinal cord has shown that distinct subpopulations of neurons express combinations of homeodomain transcription factors and that such code determines projection to specific targets. We hypothesized that a similar code of regulatory gene expression might designate the uncrossed and crossed subpopulations of RGCs. Our laboratory has discovered that a zinc-finger containing transcription factor Zic2, is expressed in RGCs with an uncrossed trajectory. Zic2, but not other Zic family members, is postmitotically but dynamically expressed in RGCs in ventrotemporal (VT) retina in the period when the uncrossed RGC subpopulation projects axons from this location toward the chiasm. Gain- and loss-of-function experiments in vitro indicate that Zic2 is necessary and sufficient to switch the outgrowth behavior of retinal axons when co-cultured with chiasm cells, from crossed to uncrossed patterns, or vice versa. Moreover, Zic2 expression correlates with the degree of binocular vision across several species. Other work in our lab has identified EphB1 as a receptor system interacting with the inhibitory factor ephrinB2 at the chiasm midline in mouse. EphB1 is expressed coincident with Zic2, spatially and temporally. The proposed work will further analyze the hypothesis that Zic2 specifies the uncrossed retinal ganglion cell axon trajectory, by regulating expression of guidance receptors in the Eph family that mediate retinal axon divergence at the optic chiasm midline.
Aims i nclude verification that Zic2 is expressed in ganglion cells with an uncrossed trajectory and elucidation of its temporal expression (Aim1); confirmation that Zic2 is necessary and sufficient to establish an uncrossed trajectory, by using loss- and gain-of-function strategies in vivo (Aim 2); investigation of Zic2's influence on genes that are putative targets, especially with regard to the EphB1 receptor in the retina (Aim 3). This analysis should shed light on patterning the binocular pathway and should apply to the establishment of bilateral sensory pathways elsewhere in the nervous system.
|Iwai-Takekoshi, Lena; Balasubramanian, Revathi; Sitko, Austen et al. (2018) Activation of Wnt signaling reduces ipsilaterally projecting retinal ganglion cells in pigmented retina. Development 145:|
|Kuwajima, Takaaki; Soares, Célia A; Sitko, Austen A et al. (2017) SoxC Transcription Factors Promote Contralateral Retinal Ganglion Cell Differentiation and Axon Guidance in the Mouse Visual System. Neuron 93:1110-1125.e5|
|Crair, Michael C; Mason, Carol A (2016) Reconnecting Eye to Brain. J Neurosci 36:10707-10722|
|Iwai-Takekoshi, Lena; Ramos, Anna; Schaler, Ari et al. (2016) Retinal pigment epithelial integrity is compromised in the developing albino mouse retina. J Comp Neurol 524:3696-3716|
|Marcucci, Florencia; Murcia-Belmonte, Veronica; Wang, Qing et al. (2016) The Ciliary Margin Zone of the Mammalian Retina Generates Retinal Ganglion Cells. Cell Rep 17:3153-3164|
|Assali, Ahlem; Gaspar, Patricia; Rebsam, Alexandra (2014) Activity dependent mechanisms of visual map formation--from retinal waves to molecular regulators. Semin Cell Dev Biol 35:136-46|
|Bhansali, Punita; Rayport, Ilana; Rebsam, Alexandra et al. (2014) Delayed neurogenesis leads to altered specification of ventrotemporal retinal ganglion cells in albino mice. Neural Dev 9:11|
|Roffler-Tarlov, Suzanne; Liu, Jin Hong; Naumova, Elena N et al. (2013) L-Dopa and the albino riddle: content of L-Dopa in the developing retina of pigmented and albino mice. PLoS One 8:e57184|
|Kuwajima, Takaaki; Sitko, Austen A; Bhansali, Punita et al. (2013) ClearT: a detergent- and solvent-free clearing method for neuronal and non-neuronal tissue. Development 140:1364-8|
|Rebsam, Alexandra; Bhansali, Punita; Mason, Carol A (2012) Eye-specific projections of retinogeniculate axons are altered in albino mice. J Neurosci 32:4821-6|
Showing the most recent 10 out of 20 publications