The DCX Superfamily 1: Common and Divergent Roles for Members of the Mouse DCX Superfamily

Abstract

The doublecortin-like (DCX) domains serve as protein-interaction platforms. DCX tandem domains appear in the product of the X-linked doublecortin (DCX) gene, in retinitis pigmentosa-1 (RP1), as well as in other gene products. Mutations in the human DCX gene are associated with abnormal neuronal migration, epilepsy, and mental retardation; mutations in RP1 are associated with a form of inherited blindness, while DCDC2 has been associated with dyslectic reading disabilities. Motivated by the possible importance of this gene family, a thorough analysis to detect all family members in the mouse was conducted. The DCX-repeat gene superfamily is composed of eleven paralogs, and we cloned the DCX domains from nine different genes. Our study questioned which functions attributed to the DCX domain, are conserved among the different members. Our results suggest that the proteins with the DCX-domain have conserved and unique roles in microtubule regulation and signal transduction. All the tested proteins stimulated microtubule assembly in vitro. Proteins with tandem repeats stabilized the microtubule cytoskeleton in transfected cells, while those with single repeats localized to actin-rich subcellular structures, or the nucleus. All tested proteins interacted with components of the JNK/MAP-kinase pathway, while only a subset interacted with Neurabin 2, and a nonoverlapping group demonstrated actin association. The sub-specialization of some members due to confined intracellular localization, and protein interactions may explain the success of this superfamily.

Mice lacking doublecortin and doublecortin-like kinase 2 display altered hippocampal neuronal maturation and spontaneous seizures

“…These seizures temporally led to a secondary loss of the SOMϩ class of inhibitory interneurons, further altering the balance of excitation and inhibition. The DCX family members are key regulators of the neuronal cytoskeleton (12), which is critical for migration and establishment of neuronal morphology. We hypothesize that cytoskeletal alterations contribute to the epileptogenic transformation of the hippocampus in the Dcx; Dclk2 null mouse (Fig.…”

A theoretical molecular network for dyslexia: integrating available genetic findings

“…65,78,79 DCDC2 encodes a protein with two DCX domains. The known function of DCX domains is that they associate with, bundle and stabilize neuronal microtubules, which are essential for neurite outgrowth and neuronal migration.…”

“…The known function of DCX domains is that they associate with, bundle and stabilize neuronal microtubules, which are essential for neurite outgrowth and neuronal migration. 12,13,69,[78][79][80] The DCX domains are also 'regulated' through phosphorylation by MAP kinase proteins such as the extracellular signalregulated kinase 1 (ERK1) and 2 (ERK2) proteins.…”

“…Within the human brain, DCDC2 is expressed, among others, in regions that are implicated in reading ability. 65,78,79,81 Finally, as with DYX1C1 (see above), in utero RNA interference against the rat homolog of DCDC2 results in neuronal migration anomalies that are similar to those seen in a small set of post-mortem brains in humans with dyslexia (see Rosen et al 58 and references herein 65,81 ). KIAA0319 was identified as a dyslexia candidate gene in two independent positional association (Table 3).…”

The doublecortin-related genezyg-8is a microtubule organizer inCaenorhabditis elegansneurons

“…Doublecortin promotes selective assembly and stability of 13-protofilament (13-pf) MTs in vitro, through the maintenance of lateral and longitudinal contacts between adjacent protofilaments (Fourniol et al, 2010;Moores et al, 2004). Many DCDCs also induce microtubule bundling when overexpressed in mammalian cells, suggesting that this family of proteins may also mediate intermolecular interactions between adjacent MTs (Bielas et al, 2007;Coquelle et al, 2006). To date, however, the contribution of DCDC proteins to MT organisation in post-mitotic cells such as neurons is poorly documented.…”