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Thesis Advisor: Emanual DiCicco-Bloom, MD
Graduate Program: Cell & Developmental Biology
Research Tower, V-10
Thursday, May 27, 2010
ENGRAILED-2 (EN2) has been associated with Autism Spectrum Disorder (ASD) in 3 different datasets. En2 is expressed in the embryo in the mid-hindbrain region where monoamine neurons originate, raising the possibility that it may be important for monoamine neuron development. Significantly, ASD patients exhibit abnormalities in monoamine levels and developmental time-course, while monoamine-modulating drugs are used for ASD therapy. Thus, to study the role of En2 in monoamine system development, we have used the En2 KO mouse model. Since forebrain abnormalities, including changes in brain size and complex behaviors, are observed in ASD patients, we focused attention on the consequences of En2 deletion on forebrain development. The monoamine neurotransmitters, especially norepinephrine and serotonin, were reduced in the forebrain but increased in the mid-hindbrain region during early postnatal development in En2 KO. These changes were due to alterations in the pattern of axonal innervation. Furthermore, the deficits in forebrain monoamines were associated with reductions in forebrain structures. In particular, reduced hippocampal size and monoamine innervation were paralleled by a decrease in granule neuron number. Moreover, En2 KO animals exhibited sex-dependent depression-like behaviors, apparently related to the neurotransmitter deficits. This study suggests a mechanism by which a mid-hindbrain patterning gene affects forebrain development and functions relevant to ASD.