Genetic Enhancement of the Lis1+/– Phenotype by a Heterozygous Mutation in the Adenomatous Polyposis Coli Gene

Abstract

Hemizygous Lis1 mutations cause type 1 lissencephaly, a neuronal migration disorder in humans. The Lis1+/– mouse is a model for lissencephaly; mice exhibit neuronal migration defects but are viable and fertile. On an inbred genetic background, 20% of Lis1+/– mice develop hydrocephalus and die prematurely. Lis1 functions with the microtubule motor cytoplasmic dynein. Because dynactin, a dynein regulator, interacts with end-binding protein 1 (EB1) and β-catenin, two known binding partners of the adenomatous polyposis coli (APC) protein, we looked for a genetic interaction between Lis1 and APC. Mice with a heterozygous truncating mutation in APC (Min mutation) do not exhibit neuronal migration defects or develop hydrocephalus. However, the presence of the APC mutation increases the migration deficit and the incidence of hydrocephalus in Lis1+/– animals. Lis1 and dynein distribution is altered in cells derived from Min mice, and both Lis1 and dynein interact with the C terminus of APC in vitro. Together, our findings point to a previously unknown interaction between APC and Lis1 during mammalian brain development.

APC conditional knock-out mouse is a model of infantile spasms with elevated neuronal β-catenin levels, neonatal spasms, and chronic seizures

“…Eleven out of 15 identified IS risk genes (including MAGI-2/S-SCAM, FOXG1, ARX, LIS1, TSC1/2, GRIN1, GRIN2A, DCX, NR2f1 and STXBP1) associate with APC, β-catenin and Wnt signaling pathways (Table 1), (Yanai H et al 2000; Campos VE et al 2004; Guerrini R and T Filippi 2005; Khanna R et al 2007; Hebbar S et al 2008; Marshall CR et al 2008; Price MG et al 2009; Conti V et al 2011; Paciorkowski AR et al 2011; Striano P et al 2011; Go CY et al 2012; Epi KC et al 2013). Mutations in ARX, FOXG1, and TSC1/2 are predicted to affect β-catenin/Wnt signaling levels and to cause changes in neuronal migration and maturation (Mak BC et al 2003; Seufert DW et al 2005; Danesin C et al 2009).…”

Adenomatous polyposis coli is required for early events in the normal growth and differentiation of the developing cerebral cortex

“…These observations raise the possibility that Apc protein might be important for proliferation and/or the subsequent differentiation of cells in the cerebral cortex. Apc has also been implicated in cerebral cortical development via its interaction with the cytoskeletal protein Lis1 [ 21 ], indicating that Apc has functions not directly related to Wnt/β-catenin signalling.…”

Bi-allelic Loss of Human APC2, Encoding Adenomatous Polyposis Coli Protein 2, Leads to Lissencephaly, Subcortical Heterotopia, and Global Developmental Delay

“…Interestingly, a genetic interaction between Pafah1b1 and Apc in murine neuronal migration was reported, but investigations of Apc2 were not performed. 22 Finally, in postmitotic neurons, APC2 controls dendritic development by promoting microtubule dynamics through two separate microtubule binding domains. 23 It is possible that these domains function during neuronal migration to mediate leadingprocess organization.…”