Brain development is severely defective in children with lissencephaly. The highly organized distribution of neurons within the cerebral cortex is disrupted, a condition that might arise from improper migration of neuronal progenitors to their cortical destinations.

In patients with lissencephaly (smooth brain), the cortex appears as a smooth surface and translates clinically to severe mental retardation, seizures and death in early childhood.

Etiology

 lissencephaly type 1 (PAFAH1B1 mutations at 17p13.3) (MIM.607432)

• Miller-Dieker lissencephaly syndrome (deletion of 17p)

 lissencephaly type 2 (LIS2) (X-linked lissencephaly) (DCX mutations at Xq22.3-q23) (MIM.300067)

 lissencephaly type 3 (LIS3) (MIM.601160)
 Norman-Roberts type lissencephaly (RELN mutations at 7q22)

Pathogenesis

 Mutations in the lissencephaly 1 gene (LIS1) and doublecortin gene (DCX), the protein products of which localize to the centrosomal region, cause clinically overlapping lissencephalic phenotypes.

LIS1 mutations cause isolated lissencephaly sequence (ILS), a heterogeneous disorder that presents differing degrees of severe lissencephaly but no other serious malformations, and contribute to the neuronal migration defects in Miller-Dieker syndrome (MDS) or 17p13.3 deletion syndrome.

An important insight into the function of LIS1 came from studies of nuclear distribution mutants (nud) in Aspergillus nidulans. In this fungus, the single nucleus of a spore divides and migrates along linear mycelia through a process in which nuclei are pulled from the spindle-pole bodies and along microtubules in a dynein-dependent manner. Mutations in the A. nidulans LIS1 orthologue, NudF, lead to the accumulation of dynein at the plus end of microtubules.

LIS1 regulates microtubule dynamics by promoting growth and by inhibiting microtubule catastrophe, and has been shown by co-immunoprecipitation to physically interact with dynein and to regulate cytoplasmic dynein function. Moreover, dynein has an important role in regulating microtubule dynamics during cell migration, allowing the release of microtubules from the centrosome.

LIS1 could mediate nuclear movement in mammalian cells by linking the nucleus, the centrosome and the microtubule network, and by regulating the molecular motor cytoplasmic dynein by allowing its retrograde movement towards microtubule minus ends.

The role of the centrosome in cell migration in humans is further supported by the fact that LIS1 interacts with several centrosomal proteins, including NUDC, NDE1 (nudE nuclear-distribution gene E homologue 1 also known as NUDE), NDEL1 (nudE nuclear-distribution gene E homologue-like 1, also known as NUDEL), and tubulin.

NDEL1 facilitates the interaction between LIS1 and dynein and is required for dynein function, which was measured by the transport of newly synthesized microtubules from the centrosomal region to the periphery of the cell.

Furthermore, the centrosomal protein 14-3-3 , which is deleted in patients with MDS71, binds and protects CDK5-p35-phosphorylated NDEL1, possibly regulating the activity of the LIS1-NDEL1-dynein complex and linking the LIS1 and CDK5-p35 neuronal migration pathways.

 Studies on the second lissencephaly-causing protein, DCX, further highlight the role of the centrosome in neuronal migration and support the notion that nucleokinesis is dependent on this organelle.

DCX mutations cause X-linked subcortical-band heterotopia (or double cortex) in females, owing to defective migration of some neurons, and lissencephaly in male.

In migrating cells, microtubules that emanate from the centrosome form a cage-like microtubule network that surrounds the nucleus and possibly holds it in the correct position during cell movement.

DCX binds and stabilizes microtubules and interacts with LIS1, indicating that DCX and LIS1 might function together with dynein to link the centrosome and nucleus during neuronal migration.

Furthermore, the LIS1-NDEL1-dynein complex is required for the maintenance of the microtubule cage, as RNAi targeting of any of these genes leads to a disruption of this structure and the concomitant separation between the nucleus and the centrosome.

Consequently, the centrosome is tethered to the leading edge and the nucleus through the microtubule network; LIS1, positioned at the centrosome, together with DCX, which is located in the nuclear microtubule 'cage', might link the nucleus to the microtubule network and allow dynein to move the nucleus towards the centrosome.

 Lissencephaly represents just one example of centrosomal dysfunction in human neurodevelopmental disease. Defective neuronal migration is likely to affect the nervous system as a whole, and, supporting this idea, it has been suggested that neuronal migration defects underlie psychiatric disorders such as SCHIZOPHRENIA.

Truncating mutations in the disrupted-in-schizophrenia 1 gene (DISC1), which encodes a centrosomal protein that interacts with many core centrosomal proteins, are associated with psychiatric disorders and, in particular, schizophrenic pathology.

DISC1 interacts with both NDEL1 and NDE1 in yeast two-hybrid screens. This raises the possibility that both DISC1 and LIS1 are functionally connected, as both proteins can interact directly and also bind to independent sites in NDEL1, indicating that neuronal migration and psychiatric disorders might be causally related.

It has been proposed that DISC1 participates in neurite growth, and its interaction with NDEL1 seems to be physiologically relevant, as truncating mutations such as those found in patients lead to the disruption of this protein complex and impaired neurite outgrowth.

It is intriguing to speculate that lissencephaly and schizophrenia represent two ends of a phenotypic spectrum of similar types of centrosomal dysfunction in the developing nervous system. However, why different perturbations of the same system have different clinical outcomes will require further investigation.

See also

 X-linked lissencephaly (X-linked subcortical laminar heterotopia)(XLIS/SCLH) (MIM.300067)

• germline mutations of DCX

References

 Badano JL, Teslovich TM, Katsanis N. The centrosome in human genetic disease. Nat Rev Genet. 2005 Mar;6(3):194-205. PMID: #15738963#

 Kato M, Dobyns WB. Lissencephaly and the molecular basis of neuronal migration. Hum Mol Genet. 2003 Apr 2;12(Suppl 1):R89-96. PMID: #12668601#