• Mustafa Sahin MD, PhD
    • Associate Professor
    •  
    • mustafa.sahin@childrens.harvard.edu
    • Tel 617-919-6258
    • Fax 617-730-0279
    • 300 Longwood Ave CLS 14073
    • Boston MA 02115
    •  

The research in the Sahin lab is directed at understanding the cellular mechanism(s) of axon guidance and its relationship to neurological dysfunction, especially in childhood neurological diseases. There are two major lines of ongoing research in the lab. First is the role of tuberous sclerosis genes (TSC1 and TSC2) 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 intellectual disability. However, a key, unresolved issue is what causes the neurological symptoms in TSC patients. We hypothesized that the miswiring of connections between neurons may contribute to the pathogenesis of epilepsy in TSC. Over the last few years, we have identified several steps in which TSC1/2-deficiency leads to defects in axonal specification, guidance and myelination. Our work on TSC strongly suggests that protein translation in the axon is crucial for axonal development and connectivity. We showed that loss of TSC function increases SAD-A translation, leading to neurons with multiple axons. We found that Eph receptor activation suppresses mTOR activity via TSC1/2. Additionally, we demonstrated that mTOR inhibitors prevent myelination defects and neurological symptoms in a TSC mouse model. Finally, using diffusion tensor imaging, we identified defects in axonal organization and myelination in TSC patients similar to those in Tsc-deficient mice. We are now focusing on the neuronal circuits that are aberrant in the TSC brain using both conditional mouse models and imaging studies in children with 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. We have identified one mRNA (cpg15 also known as neuritin) that colocalizes with SMN protein in neurons. Loss of Smn reduces cpg15 mRNA levels and exogenous expression of cpg15 partially rescues the axon phenotype associated with Smn-deficiency.
 
To study axon guidance, 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. They also use RNA interference to study the function of certain genes in cultured neurons. 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, we are investigating the molecular mechanisms underlying neuronal connectivity and their functional consequences for neurologic disease. Our ultimate goal is to use these insights on neuronal development for treatment and prevention of problems associated with TSC, SMA and related neurological diseases.
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