SONIC HEDGEHOG AND HYPERACTIVITY DISORDERS

Children'S Hospital Of Philadelphia, Philadelphia PA

Investigators

Linked publications & trials

Abstract

The secreted protein Sonic hedgehog (Shh) is required to establish pattern of cellular growth and differentiation in many tissues during embryonic development. Within the central nervous system (CNS), Shh has been shown to be essential for the specification of diverse neuronal cell fates originating from central nervous system (CNS), Shh of the neural tube. Results from in vitro neural explant assays performed in the hick have suggested that Shh pattern ventral neuroepithelium through the establishment of a morphogenic gradient, whereby distinct cell types are induced by Shh in a concentration dependent manner. To determine whether Shh functions as a morphogen in vivo we generated transgenic mice that over-express Shh under its regulatory sequences in the floor plate of the neural tube. The rationale underlying this approach stimulates that if Shh does induce distinct cell types in a concentration dependent manner then increasing levels at its sources should shift the identity of targets along the dorsal-ventral neuraxis. Two lines of mice were generated that exhibit striking behavioral abnormalities including hyperlocomoter activity and enhanced aggression. Embryos derived from these founders will be analyzed at all levels of the neuraxis for differences in dorsal-ventral positioning of Shh induced targets. As dopaminergic neurons are targets of Shh signaling in the ventral midbrain and mice deficient in the dopamine transporter exhibit similar behavioral abnormalities, it will be important to determine whether an increase in Shh signaling in the ventral midbrain and mice deficient in the dopamine transporter exhibit similar behavioral abnormalities, it will be important to determine whether an increase in Shh signaling impacts on dopamine neurotransmission. Elevated dopaminergic tone has been shown to be a contributing factor in the manifestation of attention deficit hyperactivity disorder (ADHD), a common problem affecting 3-6% of school age children. If the over-expression of Shh results in increased dopamine neurotransmission, it may implicate the Shh signaling pathway in the etiology of ADHD.