Biology Reference
In-Depth Information
FIGURE 3.1
Major human paralogs of doublecortin. The paralogs illustrated here all have two DC
domains (N-DC depicted in yellow, C-DC in orange). Two of the four isoforms of DCLK are
represented: DCX-like and full-length DCLK, which has a kinase domain (green). DCLK
full-length has a very close homolog called DCK2. The serine/proline rich domain is
colored blue.
stop half-way through their journey through the developing cortex, creating a hetero-
topic bandof graymatter lyingbetween the cortexand the ventricle, the so-calleddouble
cortex.
DCX
y/- patients possess no functional copy of the DCX protein, resulting in
lissencephaly, in which their cortex is abnormally thick and composed of four poorly
ordered layers, and these patients exhibit more severe symptoms (
Gleeson, 2000
). Thus,
DCX is essential for migration and differentiation in human neurons. It is enriched
at the distal ends of neuronal processes and may regulate MTs in response to extracel-
lular signals in these distal zones to facilitate path finding during development (
Francis
et al., 1999; Tint, Jean, Baas, & Black, 2009
). DCX is also essential for neurogenesis
in the adult brain (
Jin, Wang, Xie, Mao, & Greenberg, 2010
).
DCX is now known to be a member of a much larger family of MAPs involved
in MT regulation during cell division, migration, and differentiation (
Fig. 3.1
).
DCX-MAPs are widely distributed evolutionarily and are often essential (
Reiner
et al., 2006
): in worms, the DCX-MAP ZYG-8 is important for MT stabilization dur-
ing asymmetric cell division in embryos (
G¨nczy et al., 2001
), and in flies, a DCX-
MAP is essential for the development of mechanotransduction machinery (
Bechstedt
et al., 2010
), demonstrating the conservation and importance of these MAPs.
Doublecortin-like kinase (DCLK), initially known as doublecortin and CaM
kinase-like 1 (DCAMKL1) (
Burgess, Martinez, & Reiner, 1999
), is the closest
homologue to human DCX. It has several splicing isoforms, with a DCX-like isoform
that is 72% identical to DCX. Full-length (FL) DCLK is a 729-amino-acid protein,
with a C-terminal serine/threonine-protein kinase domain, similar to CaM kinase II.
The similarity of DCX and DCLK is highlighted by their functional compensation in
mice, where the activity of both proteins must be perturbed to recapitulate the sever-
ity of the human lissencephaly phenotype (
Deuel et al., 2006; Kerjan et al., 2009;
Koizumi, Tanaka, & Gleeson, 2006
). In humans, DCX paralogs also include
RP1, a protein that is mutated in retinitis pigmentosa (a common form of inherited
