Sall3 plays essential roles in horizontal cell maturation through regulation of neurofilament expression levels.

The region-specific homeotic gene spalt (sal) gene plays a critical role in Drosophila development. The mammalian Sal homologous genes contain four members, and Sall3 is mainly expressed in horizontal cells. In the developing retinas of Sall3 knockout (KO) mice until around birth, horizontal precursor cells developed with comparable numbers and position; the horizontal cell marker NF160 was expressed weakly and neurite-like structure had once formed. Since Sall3-KO mice die at postnatal day 1, subsequent retinal development was examined by in vitro retinal explant culture. In the Sall3-KO retina culture, the expression of NF160 was abrogated, and neurite extension was not observed. Furthermore, Sall3-KO horizontal precursors were initially localized at the appropriate horizontal positions, but eventually moved to an abnormal site in the outer nuclear layer. Overexpression of Sall3 in retinal progenitors did not induce differentiation of retinal progenitor cells into the horizontal cell-fate, but enhanced NF160 expression and neurite extension. In addition, differentiation into Müller glia was promoted, and rod cells were severely suppressed without perturbing proliferation. In conclusion, Sall3 may not be involved in horizontal cell-fate determination, but rather functions to instruct terminal differentiation of horizontal cells and to maintain NF160 expression.