Research

Welcome the the laboratory of Nathaniel Hartman at Richard Stockton College of New Jersey. We are a developmental neurobiology group that investigates the mechanisms that control neural stem cell behavior using mouse models and embryonic stem cells. Our current projects are focused on the interrelationship between the Akt and mTOR pathways in the development of neuropathologies. For more information, please contact Dr. Hartman.

Background

The brain lies at the core of our humanity. Our understanding of our external environment is tracked and decoded by the activity of billions of neurons and glia throughout our daily lives. How we deal with external and internal stimuli determines who we are and what makes us human. Alterations in the number of these cells as well as how they connect and talk to each other can profoundly impact these functions and the lives of many people.

The brain arises during embryonic development from the proliferation and differentiation of neural stem cells. These cells will form all the neurons and glia present in the adult brain. In this way, they act as the building blocks of neuronal structures and circuits. Our attention has been focused on how internal signaling mechanisms direct the fate decisions of these neural stem cells: when to divide, differentiate, migrate and ultimately what type of cell they become.

A particular pathway of interest is the protein kinase b/ mammalian target of rapamycin (Akt/mTOR) pathway. mTOR, especially, is a convergence point in cell signaling for metabolic processes and growth factor signaling. mTOR ultimately controls protein translation by inhibiting proteins that disrupt the formation of the cap binding complex. Activation of Akt/mTOR increases cap-dependent translation and encourages cellular growth, proliferation and survival.

 

Akt mTOR

Cap Dependent Translation The Akt/mTOR Pathway. Growth factor signaling stimulates the activation of Akt, which in turn inhibits the TSC1/TSC2 complex. This allows Rheb to bind to GTP which stimulates the mTOR Complex 1 (mTORC1). Activation of mTORC1 leads to a number of downstream events including the recruitment of the cap binding complex that allows for the tranlsation of a number of mRNAs. Illustrations by Alex Finger.

 

Importantly, mTOR dysregulation can lead to many neurological disorders including Tuberous Sclerosis (TSC), autism spectrum disorder, and Alzheimer’s disease. In the majority of TSC patients, mutations in either the Tsc1 or Tsc2 genes leads to mTOR hyperactivation. Patients can develop cortical lesions, dysregulated synaptic function, and slow growing tumors in their central nervous system. Over three quarters of patients experience epilepsy and more than half of affected children exhibit cognitive deficits including autism spectrum disorder.

Neural stem cells (green) derived from Sox1-GFP embryonic stem cells. Neural stem cells express nestin (red) and can divide (magenta) to give rise to both neurons and glia.

Neural stem cells (green) derived from Sox1-GFP embryonic stem cells. Neural stem cells express nestin (red) and can divide (magenta) to give rise to both neurons and glia.

Our work focuses on how the Akt/mTOR pathways impact early postnatal development. Using targeted genetic approaches such as electroporation and transgenic animals, we re investigating how dysregulation of these critical cellular components influence differentiation and migration events in postnatal neural stem cells. In addition, we are using neural stem cells derived from embryonic stem cells to measure transcriptome level changes that occur during mTOR hyperactivation.