Scrambler mouse explained

Scrambler is a spontaneous mouse mutant lacking a functional DAB1 gene, resulting in a phenotype resembling that seen in the reeler mouse.^[1] The strain was first described by Sweet et al. in 1996.^[2]

Neuroanatomical abnormalities

The spontaneous autosomal recessive scrambler mutation on chromosome 4 causes a deficiency of DAB1, encoding disabled-1, a protein involved in the signaling of the Reelin protein, lacking in the reeler mutant,^[3] Dab1-scm homozygous mutants possess a reeler-like phenotype with respect to cell malpositioning in cerebellar cortex, hippocampus, and neocortex.^{[4] [5]} Purkinje cell and granule cell degeneration results in ataxia.^[6] Despite normal Reln mRNA levels, Dab1-scm mutants have defective reelin signaling, indicating that disabled-1 acts downstream of reelin. Cell ectopias are identical with targeted disruption of Dab1.^{[7] [8]}

Behavioral abnormalities

Dab1-scm mutants have a widespread gait obvious to the naked eye (ataxia). In their home-cage, they often reel and fall, especially when attempting to rear up against the walls. Nevertheless, the mutants are fertile, and so can be reproduced from one generation to the next. Relative to non-ataxic controls of the same background strain, Dab1-scm mutants were impaired in the Rotarod Performance test of motor coordination and a grid-climbing test.^[9] When picked up by the tail, they show a pathological reflex, limb-clasping, characterized by holding together fore- or hind-limbs, or all four together in a bat-like posture.^[10]

Dab1-scm mutants were distinguished from non-ataxic controls as early as postnatal day 8 based on body tremor, gait anomalies, and body weight.^[11] On postnatal day 15, motor coordination deficits were evident on horizontal bar and inclined or vertical grid tests in association with a weaker grip strength. Further differences were detected on postnatal day 22 and evaluation at the adult age revealed impairments indicative of permanent motor alterations.

As adults, Dab1(scm) mutants showed motor coordination impairments on stationary beam, coat-hanger, and rotorod tests but were more active in the open-field. Dab1(scm) mutants were also less anxious in the elevated plus-maze but with higher latencies in the emergence test. In mutants versus controls, changes in regional brain metabolism as measured by cytochrome oxidase (COX) activity occurred mainly in structures intimately connected with the cerebellum.^[12]

In addition to motor deficits, adult Dab1-scm mutants are characterized by anomalies in grooming behavior, in particular shorter grooming bouts than non-ataxic controls of the same background strain, though they display the normal cephalocaudal sequence of grooming anterior body parts (face washing and forelimb licking) prior to posterior parts.^[13] Dab1-scm mutants are also characterized by reduced spontaneous alternation rates and deficits in visuomotor control while swimming towards a visible platform.^[14]

Notes and References

1. González JL, Russo CJ, Goldowitz D, Sweet HO, Davisson MT, Walsh CA. Birthdate and cell marker analysis of scrambler: a novel mutation affecting cortical development with a reeler-like phenotype. J Neurosci 17, 9204–11, 1997,
2. Sweet HO, Bronson RT, Johnson KR, Cook SA, Davisson MT. Scrambler, a new neurological mutation of the mouse with abnormalities of neuronal migration. Mamm Genome 7, 798–802, 1996,
3. Rice DS, Sheldon M, D'Arcangelo G, Nakajima K, Goldowitz D, Curran T. Disabled-1 acts downstream of Reelin in a signaling pathway that controls laminar organization in the mammalian brain. Development 125, 3719-29, 1998,
4. Sheldon M, Rice DS, D'Arcangelo G, Yoneshima H, Nakajima K, Mikoshiba K, Howell BW, Cooper JA, Goldowitz D, Curran T. Scrambler and yotari disrupt the disabled gene and produce a reeler-like phenotype in mice. Nature 389, 730-3, 1997,
5. Weiss KH, Johanssen C, Tielsch A, Herz J, Deller T, Frotscher M, Förster E. Malformation of the radial glial scaffold in the dentate gyrus of reeler mice, scrambler mice, and ApoER2/VLDLR-deficient mice. J Comp Neurol 460, 56-65, 2003, .
6. Goldowitz D, Cushing RC, Laywell E, D'Arcangelo G, Sheldon M, Sweet HO, Davisson M, Steindler D, Curran T. Cerebellar disorganization characteristic of reeler in scrambler mutant mice despite presence of reelin. J Neurosci 17: 8767-77, 1997,
7. Gallagher E, Howell BW, Soriano P, Cooper JA, Hawkes R. Cerebellar abnormalities in the disabled (mdab1-1) mouse. J Comp Neurol 402, 238-51, 1998,
8. Howell BW, Hawkes R, Soriano P, Cooper JA. Neuronal position in the developing brain is regulated by mouse disabled-1. Nature 389, 733-7, 1997,
9. Lalonde R, Strazielle C. Sensorimotor learning in Dab1(scm) (scrambler) mutant mice. Behav Brain Res 218, 350-2, 2011,
10. Lalonde R, Strazielle C. Brain regions and genes affecting limb-clasping responses. Brain Res Rev 67, 252-9, 2011,
11. Jacquelin C, Strazielle C, Lalonde R. Neurologic function during developmental and adult stages in Dab1(scm) (scrambler) mutant mice. Behav Brain Res 226, 265-73, 2012.
12. Jacquelin C, Lalonde R, Jantzen-Ossola C, Strazielle C. Neurobehavioral performances and brain regional metabolism in Dab1(scm) (scrambler) mutant mice. Behav Brain Res 252, 92-100, 2013.
13. Lalonde R, Lefebvre A, Jacquelin C, Strazielle C. Abnormal grooming activity in Dab1-scm (scrambler) mutant mice. Behav Brain Res 233: 24-28, 2012.
14. Jacquelin C, Strazielle C, Lalonde R. Spontaneous alternation and spatial learning in Dab1scm (scrambler) mutant mice. Brain Res Bull 87, 383-86, 2012.