Mustafa Sahin, MD, PhD
Associate Professor in Neurology, Harvard Medical School
Assistant in Neurology, Boston Children’s Hospital
The research in the Sahin lab is directed at understanding the cellular mechanism(s) of axon guidance and its relationship to neurological dysfunction. There are two major lines of ongoing research in the lab. First is the role of tuberous sclerosis genes in axons. Tuberous sclerosis (TSC) is a multi-system autosomal dominant disease, which is characterized by the formation of benign tumors (hamartomas) in several organs. The brain is almost invariable affected and patients can present with epilepsy, autism and mental retardation. However, a key, unresolved issue is what causes the neurological symptoms in TSC patients. Dr. Sahin's lab hypothesizes that the miswiring of connections between neurons may contribute to the pathogenesis of epilepsy in TSC.
The second major line of ongoing research is the role of axonopathy in spinal muscular atrophy (SMA). SMA is an autosomal recessive disease characterized by hypotonia and muscle weakness due to loss of the spinal motor neurons. Molecular genetic studies has revealed that mutations in Smn1 gene are responsible for this disease, and the SMN protein is involved in RNA processing. Despite these advances, little is known regarding the exact role of SMN in nervous system function and the nature of the RNA processing defects that underlie SMA pathology have remained elusive. Recently, it was reported by several different groups that SMN is localized to the axon and the growth cone. Furthermore, in the absence of full-length SMN, the axons are shorter, and the growth cones are smaller. Taken together, these findings suggest that dysregulation of RNA transport or translation may underlie SMA pathology.
To study axon guidance, the lab utilizes a variety of in vivo and in vitro assays and molecular and biochemical techniques. They use neurons in dissociated or organotypic cultures as well as axon tracing experiments using fluorescently labeled tracers, and they take advantage of mouse models of neurological disease and generate neuronal cultures from these mice. They also use RNA interference to study the function of certain genes in cultured neurons. Fluorescent microscopy and state-of-the-art high-resolution confocal microscopy of cultured neurons is used to examine the cytoskeleton of axons and their growth cones. In addition, they are employing biochemical analyses to quantitatively measure the relative abundance of proteins and RNA in isolated fractions and complexes. Employing these varied techniques, Dr. Sahin is examining the molecular regulation of axon guidance and the functional consequences for neurologic disease.