Sahni Lab

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Laboratory for Cell Fate Specification and Circuit Development

Paralysis is the leading cause of disability worldwide for which there are no FDA approved therapies available. Curing neurological disability to restore function ultimately requires either repairing damaged neural circuitry or recruiting intact circuits to take on new function(s). Our research goal is to identify molecules that can be recruited toward both these strategies. To identify such candidate molecules, we investigate developing circuits to identify the molecular mechanisms that control their appropriate assembly and recruit these molecules in a systematic manner toward appropriate forms of nervous system repair.

For this, we use molecular approaches including transgenic mice, CRISPR–mediated gene editing, in utero electroporation to alter gene expression, viral-mediated gene transfer, and molecular profiling (transcriptomics, epigenomics), along with precision surgery using ultrasound-guided backscatter microscopy, high throughput imaging, mouse models of central nervous system injury and disease, and behavior.

Our current focus is the corticospinal circuit, which connects the cerebral cortex with spinal circuits. It is the principal motor system responsible for voluntary movement and hence has significant clinical interest. We have identified novel genes that control development of specific aspects of its complex connectivity. We now aim to test these candidate genes toward specific forms of corticospinal circuit repair.

Sahni Lab - Figure 1

IN UTERO GENE MANIPULATION TO IDENTIFY MECHANISMS CONTROLLING CORTICOSPINAL CONNECTIVITY
IMAGE 1 LEGEND: LEFT: AN ULTRASOUND IMAGE OF A DEVELOPING MOUSE BRAIN ET EMBRYONIC DAY 12.5. THE DEVELOPING CEREBRAL CORTEX THE STRIP OF WHITE (ARROW) SURROUNDING THE LATERAL VENTRICLES (THE LARGE BLACK “HOLES”; EMPTY ARROW) WHICH ARE FLUID FILLED CAVITIES ENCASED BY THE DEVELOPING BRAIN. A PIPETTE IS USED TO INJECT RECOMBINANT DNA FOR GENE MANIPULATION. ON THE RIGHT ARE IMAGES OF A POSTNATAL MOUSE BRAIN THAT UNDERWENT SUCH MANIPULATION IN UTERO. THE TOP PANEL IS A TOP VIEW. THE MANIPULATED AREA OF THE CORTEX (GREEN; EMPTY ARROW) SHOWS EGFPEXPRESSING NEURONS. THE LOWER PANEL IS THE SAME BRAIN VIEWED FROM THE BOTTOM. LABELED CORTICOSPINAL AXONS ARE SEEN EXITING THE CORTEX AS THEY TRAVERSE TO THE SPINAL CORD (ARROW).

Sahni Lab - Figure 2

KLHL14 LIMITS CORTICOSPINAL AXON EXTENSION
IMAGE 2 LEGEND: SAGITTAL SECTIONS OF THE SPINAL CORD FROM MICE THAT UNDERWENT IN UTERO ELECTROPORATION WITH EITHER CONTROL SHRNA (CONTROL) OR KLHL14 SHRNA (EXPERIMENTAL). ROSTRAL IS TO THE TOP AND DORSAL TO THE LEFT. NOTE THAT KLHL14 SHRNA RESULTS IN CORTICOSPINAL AXONS EXTENDING SIGNIFICANTLY FURTHER INTO THE THORACIC CORD.



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Vibhu Sahni, Ph.D.

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