The evolving doublecortin (DCX) superfamily

Abstract

Background: Doublecortin (DCX) domains serve as protein-interaction platforms. Mutations in members of this protein superfamily are linked to several genetic diseases. Mutations in the human DCX gene result in abnormal neuronal migration, epilepsy, and mental retardation; mutations in RP1 are associated with a form of inherited blindness, and DCDC2 has been associated with dyslectic reading disabilities.

Results: The DCX-repeat gene family is composed of eleven paralogs in human and in mouse. Its evolution was followed across vertebrates, invertebrates, and was traced to unicellular organisms, thus enabling following evolutionary additions and losses of genes or domains. The N-terminal and C-terminal DCX domains have undergone sub-specialization and divergence. Developmental in situ hybridization data for nine genes was generated. In addition, a novel co-expression analysis for most human and mouse DCX superfamily-genes was performed using high-throughput expression data extracted from Unigene. We performed an in-depth study of a complete gene superfamily using several complimentary methods.

Conclusion: This study reveals the existence and conservation of multiple members of the DCX superfamily in different species. Sequence analysis combined with expression analysis is likely to be a useful tool to predict correlations between human disease and mouse models. The sub-specialization of some members due to restricted expression patterns and sequence divergence may explain the successful addition of genes to this family throughout evolution.

Figure 1

A. Schematic representation of human and mouse proteins containing DCX domains. DCX domains more similar to the N-terminal repeat of DCX were labeled in green, whereas those more similar to the C-terminal repeat were labeled in purple. Protein kinase domains are marked in yellow. The ricin domain is marked in brown. Human proteins are positioned on the top, the mouse proteins are shown below. B. Schematic presentation of the chromosomal location of the human and mouse DCX domain genes using UCSC site [51].

Figure 2

Maximum Likelihood (ML) phylogenetic tree including DCX domain proteins from human and mouse, bootstrap values are indicated.

Figure 3

ML tree of the tandem DCX domain proteins from different species. Bootstrap values are indicated.

Figure 4

Sequence logos of the N-terminal and C-terminal DCX motifs. Multiple alignments of the motifs from the DCX motifs are shown as sequence logos. The height of each amino acid represents bits of information and is proportional to its conservation at that position (y-axis), after the sequences have been weighted and frequencies adjusted by the expected amino acid frequency. Below the logos is the numbering of amino acids within the internal A-D subdomains. This SeqLogo represents the Lawrence Gibbs sampler motif-finding algorithm.

Figure 5

In situ hybridization patterns of genes containing the DCX protein domain. Blue stain denotes expression of the gene whose name is indicated in each panel. For details see Text. (A-D) Sagittal sections of whole E14.5 embryos. (E-H) Expression in frontal cortex. Note a few cells expressing in the ventricular zone. (I-K) Striking localized expression of BAC26042 (I), FLJ46154 (J), and Dcdc2A (K) in the E14.5 brain. In (I) "t" becomes "th" for thalamus. (L-Q) Expression patterns in the E14.5 eye. Abbreviations: cerebellum (cb), choroids plexus (cp), cortex (cx), dorsal root ganglia (drg), hypothalamus (h), inner neuroblastic layer (inl), midbrain (mb), muscles (m), olfactory epithelium (oe), outer neuroblastic layer (onl), pons (p), preplate (pp), septum (s), spinal cord (sc), thalamus (th), thymus (ty). tongue (t), ventricular zone (VZ).

Figure 6

A) Clustered Unigene [33] gene-tissue expression data. B) Gene-gene correlations based on Unigene expression data.