Agenesis of the corpus callosum: genetic, developmental and functional aspects of connectivity.

California Institute of Technology, MC 228-77 Pasadena, California 91125, USA.
Nature reviews. Neuroscience (Impact Factor: 31.38). 05/2007; 8(4):287-99. DOI: 10.1038/nrn2107
Source: PubMed

ABSTRACT Agenesis of the corpus callosum (AgCC), a failure to develop the large bundle of fibres that connect the cerebral hemispheres, occurs in 1:4000 individuals. Genetics, animal models and detailed structural neuroimaging are now providing insights into the developmental and molecular bases of AgCC. Studies using neuropsychological, electroencephalogram and functional MRI approaches are examining the resulting impairments in emotional and social functioning, and have begun to explore the functional neuroanatomy underlying impaired higher-order cognition. The study of AgCC could provide insight into the integrated cerebral functioning of healthy brains, and may offer a model for understanding certain psychiatric illnesses, such as schizophrenia and autism.

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    ABSTRACT: The corpus callosum connects cerebral hemispheres and is the largest axon tract in the mammalian brain. Callosal malformations are among the most common congenital brain anomalies and are associated with a wide range of neuropsychological deficits. Crossing of the midline by callosal axons relies on a proper midline environment that harbors guidepost cells emitting guidance cues to instruct callosal axon navigation. Little is known about what controls the formation of the midline environment. We find that two components of the Hippo pathway, the tumor suppressor Nf2 (Merlin) and the transcriptional coactivator Yap (Yap1), regulate guidepost development and expression of the guidance cue Slit2 in mouse. During normal brain development, Nf2 suppresses Yap activity in neural progenitor cells to promote guidepost cell differentiation and prevent ectopic Slit2 expression. Loss of Nf2 causes malformation of midline guideposts and Slit2 upregulation, resulting in callosal agenesis. Slit2 heterozygosity and Yap deletion both restore callosal formation in Nf2 mutants. Furthermore, selectively elevating Yap activity in midline neural progenitors is sufficient to disrupt guidepost formation, upregulate Slit2 and prevent midline crossing. The Hippo pathway is known for its role in controlling organ growth and tumorigenesis. Our study identifies a novel role of this pathway in axon guidance. Moreover, by linking axon pathfinding and neural progenitor behaviors, our results provide an example of the intricate coordination between growth and wiring during brain development.
    Journal of Cell Science 11/2014; 141(21):4182-93. · 5.33 Impact Factor
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    ABSTRACT: Abstract OBJECTIVE: To ascertain the incidence and clinical implications of agenesis of the corpus callosum (ACC) in spinal open neural tube defects (SONTD). METHODS: All cases of SONTD registered at the Spina Bifida Clinic in King Khalid University Hospital, Riyadh, Saudi Arabia between 1995 and 2010 were retrospectively reviewed, and mid-sagittal MRI of the corpus callosum (CC) area was analyzed in each case. Neurodevelopmental outcome was classified as poor in children with seizures, severe neurodevelopmental impairment, or death. RESULTS: Thirty-eight patients (45.8%) with ACC were identified among 83 cases with SONTD. Patients' age ranged between one and 16 years. Total ACC was found in 10 patients, partial ACC in 25, and in 3 patients, the CC was hypoplastic. Active hydrocephalus was an associated finding in 9 out of 10 patients with total ACC, 22 out of 25 with partial ACC, and in all patients with hypoplasia of the CC. Thirteen patients (34.2%) had normal intellectual function, whereas 24 patients presented with learning disability, epilepsy, or poor intellectual function; and one patient died of respiratory failure. CONCLUSION: Agenesis of the corpus callosum is found in a significant portion of patients with SONTD. When associated with hydrocephalus, its presence affects neuro-developmental outcome.
    Saudi medical journal 12/2014; 35(12):S57-63.. · 0.55 Impact Factor
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