LNX1 and LNX2 are E3 ubiquitin ligases that can interact with Numb a key regulator of neurogenesis and neuronal differentiation. LNX1 can target Numb for proteasomal degradation, and Lnx mRNAs are prominently expressed in the nervous system, suggesting that LNX proteins play a role in neural development. This hypothesis remains unproven, however, largely because LNX proteins are present at very low levels in vivo. Here, we demonstrate expression of both LNX1 and LNX2 proteins in the brain for the first time. We clarify the cell-type specific expression of LNX isoforms in both the CNS and PNS, and identify a novel LNX1 isoform. Using luciferase reporter assays, we show that the 5' untranslated region of the Lnx1_variant2 mRNA, that generates the LNX1p70 isoform, strongly suppresses protein production. This effect is mediated in part by the presence of upstream open reading frames (uORFs), but also by a sequence element that decreases both mRNA levels and translational efficiency. By contrast, uORFs do not negatively regulate LNX1p80 or LNX2 expression. Instead, we find some evidence that protein turnover via proteasomal degradation may influence LNX1p80 levels in cells. These observations provide plausible explanations for the low levels of LNX1 proteins detected in vivo. (C) 2014 Elsevier B.V. All rights reserved.