Genetic causes of microcephaly and lessons for neuronal development
Edward C Gilmore1, Christopher A Walsh
1Division of Pediatric Neurology, Department of Pediatrics, Case Western Reserve University, Cleveland, OH, USA.
Wiley Interdisciplinary Reviews. Developmental Biology
|September 10, 2013
Summary
Developmental microcephaly research reveals how brain cell production impacts size. Genetic mutations, particularly affecting centrosomes and DNA repair, disrupt neuron numbers, offering insights into brain development and evolution.
Area of Science:
- Neuroscience
- Developmental Biology
- Genetics
Background:
- Developmental microcephaly offers critical insights into human brain development and neuron production.
- Abnormalities in cellular production, particularly affecting neuron numbers, are central to microcephaly's pathophysiology.
- Primary microcephaly is frequently linked to centrosomal abnormalities, crucial for cell division.
Purpose of the Study:
- To explore the role of centrosomal and DNA repair pathways in determining brain size during development.
- To understand the specialized functions of centrosomes in neuronal production within the brain.
- To investigate the evolutionary significance of microcephaly-associated genes in primate and human brain evolution.
Main Methods:
- Analysis of genetic causes of primary developmental microcephaly.
- Examination of centrosomal protein functions in cell proliferation and mitosis.
- Review of evolutionary selection evidence for microcephaly genes.
- Investigation of DNA repair pathways and their impact on brain development.
Main Results:
- Centrosomal abnormalities are a common cause of primary microcephaly, impacting the mitotic spindle and cell proliferation.
- Mutations in microcephaly genes suggest unique centrosomal functions in neuronal production, though models are debated.
- Some microcephaly genes show evolutionary selection, indicating roles in regulating neuron number and brain volume across species.
- Mutations in DNA repair genes also cause microcephaly, with double-stranded DNA breaks being a key issue.
Conclusions:
- Understanding microcephaly pathophysiology illuminates fundamental mechanisms of brain development and neuron generation.
- Centrosome and DNA repair pathways are critical for normal brain size, with potential specialized roles in the brain.
- Further research is needed to clarify the precise relationship between DNA repair, centrosome function, and the brain's unique susceptibility to these defects.
