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Spinal muscular atrophy (SMA) is caused by low survival motor neuron (SMN) levels and patients represent a clinical spectrum due primarily to varying copies of the  survival motor neuron-2  ( SMN2 ) gene. Patient and animals studies show that disease severity is abrogated as SMN levels increase. Since therapies currently being pursued target the induction of SMN, it will be important to understand the dosage, timing and cellular requirements of SMN for disease etiology and potential therapeutic intervention. This requires new mouse models that can induce SMN temporally and/or spatially. Here we describe the generation of two hypomorphic  Smn  alleles,  Smn C-T-Neo   and  Smn 2B-Neo  . These alleles mimic  SMN2  exon 7 splicing, titre Smn levels and are inducible. They were specifically designed so that up to three independent lines of mice could be generated, herein we describe two. In a homozygous state each allele results in embryonic lethality. Analysis of these mutants indicates that greater than 5% of Smn protein is required for normal development. The severe hypomorphic nature of these alleles is caused by inclusion of a  loxP -flanked  neomycin  gene selection cassette in  Smn  intron 7, which can be removed with Cre recombinase.  In vitro  and  in vivo  experiments demonstrate these as inducible  Smn  alleles. When combined with an inducible  Cre  mouse, embryonic lethality caused by low Smn levels can be rescued early in gestation but not late. This provides direct genetic evidence that a therapeutic window for SMN inductive therapies may exist. Importantly, these lines fill a void for inducible  Smn  alleles. They also provide a base from which to generate a large repertoire of SMA models of varying disease severities when combined with other  Smn  alleles or  SMN2 -containing mice.

Mouse Survival Motor Neuron Alleles That Mimic SMN2 Splicing and Are Inducible Rescue Embryonic Lethality Early in Development but Not Late