Sonic Hedgehog Determines Early Retinal Development and Adjusts Eyeball Architecture

The eye primordium of vertebrates initially forms exactly at the side of the head. Later, the eyeball architecture is tuned to see ahead with better visual acuity, but its molecular basis is unknown. The position of both eyes in the face alters in patients with holoprosencephaly due to <i>Sonic hedgehog</i> (<i>Shh</i>) mutations that disturb the development of the ventral midline of the neural tube. However, patient phenotypes vary extensively, and microforms without a brain anomaly relate instead to alternation of gene expression of the Shh signaling center in the facial primordia. We identified novel missense mutations of the <i>Shh</i> gene in two patients with a dislocated fovea, where the photoreceptor cells are condensed. Functional assays showed that Shh upregulates <i>Patched</i> and <i>Gli</i> and downregulates <i>Pax6</i>, and that <i>Shh</i> mutations alter these activities. Gain of function of Shh in a chick embryo retards retinal development and eyeball growth depending on the location of Shh expression, while loss of function of Shh promotes these features. We postulate that a signaling molecule like Shh that emanates from the face controls the extent of differentiation of the neural retina in a position-specific manner and that this may result in the formation of the fovea at the correct location.