Brain Development

The integrity of the central nervous system (CNS) relies on the production of the correct number of neurons and their correct positioning.  Our prior work demonstrated that alterations in the cell division plane of neural progenitors could markedly impact the size of the progenitor pool and the final number of neurons produced.  Currently, we are investigating the roles of several neurological disease genes, including those contributing to human microcephaly and lissencephaly, neurogenesis and neuronal migration. 

Neuropsychiatric disorders

It should be noted that abnormal architecture of the brain is implicated in other neurological disorders including autism, epilepsy and psychiatric diseases.  The Disrupted in Schizophrenia 1 (DISC1) gene is implicated in schizophrenia, bipolar disorder and major depression.  DISC1 encodes a large scaffold protein that interacts with several distinct signaling pathways.  The function of the DISC1 gene product has been associated with neuronal migration, neurite outgrowth, and integration of new neurons during adult neurogenesis.  We are assessing the role of DISC1 in controlling the number of neurons produced during embryonic and adult neurogenesis.   Understanding the signaling events it regulates during brain development may help uncover novel therapeutic strategies against psychiatric disorders.

Alzheimer’s disease

Alzheimer’s disease is a devastating and irreversible brain disorder that eventually leads to dementia.  Cyclin-dependent kinase 5 (Cdk5), a small protein serine/threonine kinase, plays an important role in brain development, including neuronal migration, axon/dendrite morphogenesis, and dendritic spine/synapse formation.  Using mouse genetics to abolish Cdk5 expression in specific regions of the hippocampus, we found that Cdk5 is essential for hippocampus- dependent memory formation.  However, Cdk5 is also key to neuronal demise when hyperactivated due to the accumulation of p25, an activator of Cdk5.  Transgenic mice expressing p25 develop rapid and severe neurodegeneration including tau and b-amyloid pathology ,and exhibit learning impairments.  We recently showed that the learning impairments and memory loss could be markedly attenuated when the p25 transgenic mice were treated with general inhibitors of histone deacetylases (HDAC), which results in chromatin remodeling.  Currently, we are investigating new approaches that allow attenuation of neurodegeneration and recovery of learning impairments using the p25 transgenic mouse model.

 

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