Uncovering molecular mechanisms of microcephaly

Authors

• T Schoborg
• L Smith
• S Smith
• Y Yu
• C Fagerstrom
• T Lee
• NM Rusan

Abstract

Autosomal recessive primary microcephaly (MCPH) is a neurodevelopmental disorder characterized by reduced brain size and life span. While the clinical aspects of the disorder are well characterized, the molecular mechanism remains poorly understood. The currently accepted hypothesis favors cell division defects induced by mitotic spindle errors as the cause of the disorder, as mistakes in chromosome segregation can lead to abnormal differentiation and apoptosis. Either of these scenarios can reduce neuron/glia numbers, which in turn results in a smaller brain. The most commonly mutated gene in human MCPH patients, Abnormal Spindle-Like, Microcephaly Associated (ASPM) is known to be important for proper centrosome and mitotic spindle function during mitosis. However, our recent analysis of the Drosophila melanogaster ortholog, Abnormal Spindle (Asp), showed that mitotic spindle & cell division defects are not the primary cause of MCPH in Asp mutant animals, suggesting the current model needs to be revised. To do so, we are establishing a set of criteria that defines MCPH using novel imaging methods such as microcomputed tomography (micro-CT) and optical sectioning of intact adult heads and brains, coupled with sophisticated image segmentation and registration algorithms. Our data has revealed that a null mutation of Asp specifically disrupts proper development of the adult optic lobes but not other brain regions. Surprisingly, our structure-function analysis of the protein suggest Asp may have a novel role in the interphase nucleus of mature neurons that might be important for its role in specifying proper optic lobe development and proper brain size

Scientific Focus Area: Neuroscience

This page was last updated on Friday, March 26, 2021