A genetic study of the suppressors of the Engrailed-1 cerebellar phenotype

• Published in: Brain research Vol. 1140; pp. 170 - 178
• Main Authors: Murcia, Crystal L, Gulden, Forrest O, Cherosky, Natalie A, Herrup, Karl
• Format: Journal Article
• Language: English
• Published: London Elsevier B.V 06-04-2007; Amsterdam Elsevier; New York, NY
• Subjects: Animals; Biological and medical sciences; Cerebellum - embryology; Cerebellum - metabolism; Cerebellum development; Chromosome Mapping - methods; Development. Senescence. Regeneration. Transplantation; En1; En2; Female; Fundamental and applied biological sciences. Psychology; Gene Expression Regulation, Developmental; Gene Regulatory Networks; Genetic background; Homeodomain Proteins - genetics; Homeodomain Proteins - metabolism; Lod Score; Mice; Mice, Inbred C57BL; Mice, Knockout; Modifier gene; Nerve Tissue Proteins - genetics; Nerve Tissue Proteins - metabolism; Neurology; Phenotype; Pregnancy; Rhombencephalon - embryology; Rhombencephalon - metabolism; Vertebrates: nervous system and sense organs; En2; En1; Genetic background; Modifier gene; Cerebellum development; Cerebellum; Rodentia; Central nervous system; Genetic determinism; Encephalon; Neurological mutation; Vertebrata; Phenotype; Mammalia; Gene; Mouse; Animal; Development; Genetics; En1;En2;Cerebellum development;Genetic background;Modifier gene
• ISSN: 0006-8993; 1872-6240
• DOI: 10.1016/j.brainres.2006.06.076

Abstract The mouse Engrailed genes, En1 and En2 , play an important role in the development of the cerebellum from its inception at the mid/hindbrain boundary in early embryonic development through cell type specification events and beyond. In the absence of En1 , the cerebellum and caudal midbrain fail to develop normally—a phenotype that we have previously reported to be strain dependent. On the 129/S1 strain background, En1 null alleles lead to mid/hindbrain failure, whereas on the C57BL/6 background, En1 deficiency is compatible with near normal cerebellar development. We have pursued this dramatic effect of genetic background by performing a genetic modifier screen through F1 backcross and F1 intercross matings. The backcross has yielded two strong candidate intervals with suggestive linkage to a third region. Moreover, variations in rescue frequency among subgroups within the backcross indicate gender and parent of origin influences on rescue penetrance. The intercross data reveal locus heterogeneity of the En1 modifiers, with more than one compliment of C57BL/6 and 129/S1 alleles capable of mediating the rescue phenotype. These findings highlight the complexity and plasticity of gene networks involved in brain development.