Mustafa Sahin, MD, Ph.D.

Assistant Professor of Neurology

Kirby Neurobiology Center
Children's Hospital
Center for Life Science Building
3 Blackfan Circle
Boston, MA 02115
Telephone: 617-919-4518
Fax: 617- 730-1953

email: mustafa.sahin@childrens.harvard.edu

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. Our lab has generated evidence that the miswiring of connections between neurons contributes to the pathogenesis of TSC using mouse models. The miswiring correlates with defects at the level of axonal specification, guidance and myelination. Now, we are in search of treatment options to reverse and/or prevent these defects at the cellular level.

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 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. Currently, we are characterizing role of SMN gene in axon outgrowth and guidance in vivo and searching for the RNA cargos and translationally-regulated neuronal targets of SMN.

To study axonal development, the lab utilizes a variety of in vivo and in vitro assays and molecular and biochemical techniques. We 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. In addition, we are employing biochemical analyses to quantitatively measure the relative abundance of proteins and RNA in isolated fractions and complexes. Employing these varied techniques, our lab is examining the molecular regulation of axonal development and the functional consequences for neurologic disease. Our studies of neuronal connectivity in normal- and disease-states should provide new insights into pathogenesis of common neurological problems such as autism, epilepsy and mental retardation.

References:

• Meikle L, Pollizzi K, Egnor A, Kramvis I, Lane H, Sahin M, Kwiatkowski DJ. Response of a neuronal model of tuberous sclerosis to mTOR inhibitors: effects on mTORC1 and Akt signaling lead to improved survival and function. J. Neurosci 2008;28:5422-32.
• Ozcan U, Ozcan L, Yilmaz E, Duewel K, Sahin M, Manning BD, Hotamisligil GS. Loss of Tuberous Sclerosis Complex suppressors triggers Unfolded Protein Response to regulate insulin action and cell death. Mol Cell 2008;29:541-551.
• Jeste SS, Sahin M, Bolton P, Ploubidis GB, Humphrey A. Characterization of autism in young children with Tuberous Sclerosis Complex. J. Child Neurol 2008;23:520-5.
• Meikle L, Talos DM, Onda H, Pollizzi K, Rotenberg A, Sahin M, Jensen FE and Kwiatkowski DJ. A mouse model of tuberous sclerosis: neuronal loss of Tsc1 causes dysplastic and ectopic neurons, reduced myelination, seizure activity, and limited survival. J Neurosci 2007;27:5546-58.
• Fu WY, Chen Y, Sahin M, Zhao XS, Shi L, Bikoff JB, Lai KO, Yung WH, Fu AK, Greenberg ME and Ip NY. Cdk5 regulates EphA4-mediated dendritic spine retraction through an ephexin1-dependent mechanism. Nat Neurosci 2007;10:67-76.
• Sahin M, Greer P, Lin MZ, Poucher H, Eberhart J, Schmidt S, Wright TM, Shamah SM, O'Connell S, Cowan CW, Hu L, Goldberg JL, Corfas G, Krull CE, Greenberg ME. Eph dependent tyrosine phosphorylation of ephexin1 modulates growth cone collapse. Neuron 2005;46:191-204. 

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