Opposing Shh and Fgf signals initiate nasotemporal patterning of the retina

Abstract

The earliest known determinants of retinal nasotemporal identity are the transcriptional regulators Foxg1, which is expressed in the prospective nasal optic vesicle, and Foxd1, which is expressed in the prospective temporal optic vesicle. Previous work has shown that, in zebrafish, Fgf signals from the dorsal forebrain and olfactory primordia are required to specify nasal identity in the dorsal, prospective nasal, optic vesicle. Here, we show that Hh signalling from the ventral forebrain is required for specification of temporal identity in the ventral optic vesicle and is sufficient to induce temporal character when activated in the prospective nasal retina. Consequently, the evaginating optic vesicles become partitioned into prospective nasal and temporal domains by the opposing actions of Fgfs and Shh emanating from dorsal and ventral domains of the forebrain primordium. In absence of Fgf activity, foxd1 expression is established irrespective of levels of Hh signalling, indicating that the role of Shh in promoting foxd1 expression is only required in the presence of Fgf activity. Once the spatially complementary expression of foxd1 and foxg1 is established, the boundary between expression domains is maintained by mutual repression between Foxd1 and Foxg1.

Eye morphogenesis in the blind Mexican cavefish

“…Moreover, albeit smaller, CF optic vesicles are “correctly” patterned in their future naso-temporal axis, as shown by Hernández-Bejarano and colleagues at 10/12 somite stage (~13.5hpf) using FoxG1 and FoxD1 markers ( Fig. 6A ) (Hernandez-Bejarano et al, 2015). Second, after the initial evagination and patterning of a small optic vesicle, morphogenesis proceeds with the “extended evagination”, whereby cells from the neural tube continue entering the optic vesicle to contribute exclusively to the ventro-nasal part of the eye (Kwan et al, 2012).…”

“…This is in agreement with our findings showing that the improper closure of the optic fissure is autonomous to the CF retinal tissues and results from defective morphogenetic movements. Sixth, in addition and concomitantly to impaired morphogenetic processes, morphogen signalling modifications previously reported in cavefish might contribute to the axial patterning variations observed. On the naso-temporal axis, there seems to be a slight increase in FoxG1 domain in the early optic vesicle (Hernandez-Bejarano et al, 2015), which may be explained by the earlier onset of Fgf8 expression in the cavefish anterior neural ridge (Pottin et al, 2011), but also by the increase in size of the cavefish olfactory placodes which also secrete Fgf24 (Hernandez-Bejarano et al, 2015; Hinaux et al, 2016). These Fgfs, along with Fgf3 promote retinal nasal fate (Hernandez-Bejarano et al, 2015; Picker and Brand, 2005; Picker et al, 2009), and may be responsible for the slight expansion of FoxG1 expression in cavefish, itself limited or counteracted by increased Shh signalling (Hernandez-Bejarano et al, 2015).…”

“…In the retina, several transcription factors such as Vax2 , FoxG1 , Tbx5a , or FoxD1 present a strong regional expression, already present at optic vesicle stage, and define the future quadrants identity by controlling the expression of effector guidance molecules (French et al, 2009; Picker et al, 2009; Sakuta et al, 2006; Schulte et al, 1999). The regionalized expression of the transcription factors themselves is mainly achieved through Hedgehog and Fgf signalling from the embryonic midline, and reciprocal interactions between them (Asai-Coakwell et al, 2007; Hernandez-Bejarano et al, 2015; Kruse-Bend et al, 2012; Picker and Brand, 2005; Picker et al, 2009). Shh is involved in the regulation of the ventral and temporal fates while Fgfs secreted by the anterior neural ridge and olfactory placode seem to be involved in nasal specification.…”

“…Shh is involved in the regulation of the ventral and temporal fates while Fgfs secreted by the anterior neural ridge and olfactory placode seem to be involved in nasal specification. Extra-ocular Bmps direct the acquisition of dorsal fates (Gosse and Baier, 2009; Hernandez-Bejarano et al, 2015; Picker and Brand, 2005; Picker et al, 2009; Take-uchi et al, 2003).…”

Ipsilateral and Contralateral Retinal Ganglion Cells Express Distinct Genes during Decussation at the Optic Chiasm

“…Of the known retinal guidance receptors potentially regulated by these transcriptional programs, knockout mouse models show only partial changes in laterality (Williams et al, 2003, 2006a; Erskine et al, 2011; Kuwajima et al, 2012). Moreover, the molecular interactions between transcription factors (e.g., Zic2 and Islet2), downstream effectors (e.g., EphB1, Neuropilin, NrCAM, and PlexinA1), and upstream patterning genes (e.g., Foxd1 and Foxg1) within this genetic network have proven difficult to identify, suggesting the presence of yet-unknown intermediate players that bridge these gaps (Herrera et al, 2003, 2004; Pak et al, 2004; Pratt et al, 2004; Tian et al, 2008; Picker et al, 2009; Carreres et al, 2011; Fotaki et al, 2013; Hernandez-Bejarano et al, 2015). For example, in overexpression studies, Zic2 is more potent than EphB1 in switching RGC projection laterality (Petros et al, 2009b) and thus may regulate additional downstream factors in the uncrossed guidance program.…”