Similar axon targeting errors in BACE1 and CHL1 mice 1 β-Site Amyloid Precursor Protein (APP) Cleaving Enzyme 1 (BACE1) Deficient Mice Exhibit a Close Homolog of L1 (CHL1) Loss-of-Function Phenotype Involving Axon Guidance Defects*

BACE1 is the β-secretase enzyme that initiates production of the β-amyloid (Aβ) peptide involved in Alzheimer’s disease (AD). However, little is known about functions of BACE1. BACE1 deficient mice exhibit mild but complex neurological phenotypes suggesting therapeutic BACE1 inhibition may not be completely free of mechanism-based side effects. Recently, we have reported that BACE1 null mice have axon guidance defects in olfactory sensory neuron (OSN) projections to glomeruli in the olfactory bulb. Here, we show that BACE1 deficiency also causes an axon guidance defect in the hippocampus: a shortened and disorganized infrapyramidal bundle (IPB) of the mossy fiber projection from the dentate gyrus to CA3. Although we observed that a classical axon guidance molecule, EphA4, was cleaved by BACE1 when co-expressed with BACE1 in HEK293 cells, we could find no evidence of BACE1 processing of EphA4 in the brain. Remarkably, we discovered that the axon guidance defects of BACE1 mice were strikingly similar to those of mice deficient in a recently identified BACE1 substrate, the neural cell adhesion molecule close homolog of L1 (CHL1) that is involved in neurite outgrowth. CHL1 undergoes BACE1-dependent processing in BACE1, but not BACE1, hippocampus and olfactory bulb, indicating that CHL1 is a http://www.jbc.org/cgi/doi/10.1074/jbc.M112.415505 The latest version is at JBC Papers in Press. Published on September 17, 2012 as Manuscript M112.415505