Mouse survival motor neuron alleles that mimic SMN2 splicing and are inducible rescue embryonic lethality early in development but not late
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 t...
| Main Authors: | , , , , , |
|---|---|
| Other Authors: | |
| Format: | Journal article |
| Published: |
Public Library of Science
2010
|
| _version_ | 1797074414367408128 |
|---|---|
| author | Hammond, S Gogliotti, R Rao, V Beauvais, A Kothary, R Didonato, C |
| author2 | McCabe, B |
| author_facet | McCabe, B Hammond, S Gogliotti, R Rao, V Beauvais, A Kothary, R Didonato, C |
| author_sort | Hammond, S |
| collection | OXFORD |
| description | 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, SmnC-T-Neo and Smn2B-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. |
| first_indexed | 2024-03-06T23:35:48Z |
| format | Journal article |
| id | oxford-uuid:6d9ccbb0-8202-4aa8-ba72-0e0a0c70875e |
| institution | University of Oxford |
| last_indexed | 2024-03-06T23:35:48Z |
| publishDate | 2010 |
| publisher | Public Library of Science |
| record_format | dspace |
| spelling | oxford-uuid:6d9ccbb0-8202-4aa8-ba72-0e0a0c70875e2022-03-26T19:18:58Z Mouse survival motor neuron alleles that mimic SMN2 splicing and are inducible rescue embryonic lethality early in development but not lateJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:6d9ccbb0-8202-4aa8-ba72-0e0a0c70875eSymplectic Elements at OxfordPublic Library of Science2010Hammond, SGogliotti, RRao, VBeauvais, AKothary, RDidonato, CMcCabe, BSpinal 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, SmnC-T-Neo and Smn2B-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. |
| spellingShingle | Hammond, S Gogliotti, R Rao, V Beauvais, A Kothary, R Didonato, C Mouse survival motor neuron alleles that mimic SMN2 splicing and are inducible rescue embryonic lethality early in development but not late |
| title |
Mouse survival motor neuron alleles that mimic SMN2 splicing and are inducible rescue embryonic lethality early in development but not late |
| title_full |
Mouse survival motor neuron alleles that mimic SMN2 splicing and are inducible rescue embryonic lethality early in development but not late |
| title_fullStr |
Mouse survival motor neuron alleles that mimic SMN2 splicing and are inducible rescue embryonic lethality early in development but not late |
| title_full_unstemmed |
Mouse survival motor neuron alleles that mimic SMN2 splicing and are inducible rescue embryonic lethality early in development but not late |
| title_short |
Mouse survival motor neuron alleles that mimic SMN2 splicing and are inducible rescue embryonic lethality early in development but not late |
| title_sort | mouse survival motor neuron alleles that mimic smn2 splicing and are inducible rescue embryonic lethality early in development but not late |
| work_keys_str_mv | AT hammonds mousesurvivalmotorneuronallelesthatmimicsmn2splicingandareinduciblerescueembryoniclethalityearlyindevelopmentbutnotlate AT gogliottir mousesurvivalmotorneuronallelesthatmimicsmn2splicingandareinduciblerescueembryoniclethalityearlyindevelopmentbutnotlate AT raov mousesurvivalmotorneuronallelesthatmimicsmn2splicingandareinduciblerescueembryoniclethalityearlyindevelopmentbutnotlate AT beauvaisa mousesurvivalmotorneuronallelesthatmimicsmn2splicingandareinduciblerescueembryoniclethalityearlyindevelopmentbutnotlate AT kotharyr mousesurvivalmotorneuronallelesthatmimicsmn2splicingandareinduciblerescueembryoniclethalityearlyindevelopmentbutnotlate AT didonatoc mousesurvivalmotorneuronallelesthatmimicsmn2splicingandareinduciblerescueembryoniclethalityearlyindevelopmentbutnotlate |