Disabled

DEVELOPMENTAL BIOLOGY

Embryonic

The embryonic expression pattern of Dab mRNA, examined by in situ hybridization to whole-mount embryos, shows uniform expression from blastoderm through gastrulation. At the end of germ-band extension, higher levels of Dab mRNA are detected in the mesoderm and in the CNS. Polyclonal rabbit antibody to Dab detects a similar distribution. In the cellular blastoderm, immunohistochemical staining for Dab protein is detected in the cytoplasm and not the nucleus. During gastrulation, Dab protein is broadly distributed, but is higher in the CNS. Later in development, the signal in the CNS is concentrated in axon bundles. Dab protein is also detected in PNS cell clusters and the body wall musculature (Gertler, 1993).

Effects of Mutation or Deletion

During Drosophila embryogenesis, Abl is localized in the axons of the central nervous system (CNS). Mutations in Abl have no detectable effect on the morphology of the embryonic CNS; the mutant animals survive to the pupal and adult stages. However, in the absence of Abl function, heterozygous mutations or deletions of Disabled (Dab) exert dominant effects, disrupting axonal organization and shifting the lethal phase of the animals to embryonic and early larval stages. Embryos that are homozygous mutant for both Abl and Dab fail to develop any axon bundles in the CNS, although the peripheral nervous system and the larval cuticle appear normal. The genetic interaction between these two genes begins to define a process in which both the Abl tyrosine kinase and Enabled participate in establishing axonal connections in the embryonic CNS of Drosophila (Gertler, 1989).

In the absence of the Drosophila Abl protein-tyrosine kinase (PTK), loss-of-function mutations in either Disabled or prospero have dominant phenotypic effects on embryonic development. Molecular and genetic characterizations indicate that the products of these genes interact with the Abl PTK by different mechanisms. The interaction between Abl and prospero, which encodes a nuclear protein required for correct axonal outgrowth, is likely to be indirect. In contrast, the product of Disabled may be a substrate for the Abl PTK. The Disabled protein is colocalized with Abl in axons; its predicted amino acid sequence contains 10 motifs similar to the major autophosphorylation site of Abl, and the protein is recognized by antibodies to phosphotyrosine (Gertler, 1993).

Mutations in the failed axon connections (fax) gene have been identified as dominant genetic enhancers of the Abl mutant phenotype. These mutations in fax all result in defective or absent protein product. In a genetic background with wild-type Abl function, the fax loss-of-function alleles are homozygous viable, demonstrating that fax is not an essential gene unless the animal is also mutant for Abl. The fax gene encodes a novel 47-kD protein expressed in a developmental pattern similar to that of Abl in the embryonic mesoderm and axons of the central nervous system. The conditional, extragenic noncomplementation between fax and another Abl modifier gene, Disabled, reveals that the two proteins are likely to function together in a process downstream or parallel to the Abl protein tyrosine kinase (Hill, 1995).

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date revised: 30 November 2008

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