Microphthalmos is a rare congenital anomaly characterized by reduced eye size 
and visual deficits of variable degree. Sporadic and hereditary microphthalmos 
have been associated with heterozygous mutations in genes fundamental for eye 
development. Yet, many cases are idiopathic or await the identification of 
molecular causes. Here we show that haploinsufficiency of Meis1, which encodes a 
transcription factor with evolutionarily conserved expression in the embryonic 
trunk, brain and sensory organs, including the eye, causes microphthalmic traits 
and visual impairment in adult mice. By combining analysis of Meis1 
loss-of-function and conditional Meis1 functional rescue with ChIP-seq and 
RNA-seq approaches we show that, in contrast to its preferential association 
with Hox-Pbx BSs in the trunk, Meis1 binds to Hox/Pbx-independent sites during 
optic cup development. In the eye primordium, Meis1 coordinates, in a 
dose-dependent manner, retinal proliferation and differentiation by regulating 
genes responsible for human microphthalmia and components of the Notch signaling 
pathway. In addition, Meis1 is required for eye patterning by controlling a set 
of eye territory-specific transcription factors, so that in Meis1(-/-) embryos 
boundaries among the different eye territories are shifted or blurred. We 
propose that Meis1 is at the core of a genetic network implicated in eye 
patterning/microphthalmia, and represents an additional candidate for syndromic 
cases of these ocular malformations.