Lisa Goodrich, Ph.D.
Associate Professor of Neurobiology
Department of Neurobiology
Goldenson Building, Room 442
220 Longwood Avenue
Boston, MA 02115
Visit my lab page here.
In my laboratory, we study the cellular and molecular mechanisms that govern the development of neural circuits, from the determination and differentiation of neurons to the formation of axonal connections and ultimately the generation of behavior. While the individual steps underlying circuit assembly are well described, how these relatively generic events are coordinated to create neural networks dedicated to specific functions remains unclear. We are taking advantage of recent advances in mouse molecular genetics and genomics to piece together a global view of how circuit assembly is regulated, with a focus on in vivo analysis. Many of our studies focus on the auditory system, which is poorly understood relative to the other sensory systems, despite the obvious impact of age-related and noise-induced hearing loss on our society. Additional insights into how different kinds of networks acquire their unique features come from studies of retinal circuits, which exhibit a striking laminated pattern.
Auditory Circuit Assembly: We perceive sound using precisely wired circuits that originate in the cochlea of the inner ear. The primary auditory neurons – the spiral ganglion neurons – exhibit several distinctive features that ensure that sound information is faithfully communicated from the ear to the brain. For instance, each spiral ganglion neuron bifurcates to enable parallel processing in the brainstem and elaborates enormous and unusually rapid synapses that are critical for sound localization. To learn how spiral ganglion neurons acquire these unique properties, we have catalogued the cellular and molecular events underlying auditory circuit assembly in mouse, including live imaging of spiral ganglion axon outgrowth in the intact embryonic cochlea. Currently, we are dissecting the functions of specific molecules, including a transcriptional network that guides the assembly process and a receptor that is necessary for bifurcation. Since auditory function is relatively easy to assess in mice, we are able to link any cellular changes with changes in auditory perception. These studies involve extensive creation and analysis of transgenic and mutant mouse strains, in vitro axon guidance assays, and ChiP-Seq and microarray studies to define transcriptional networks. Auditory function is assessed using the auditory brainstem response recording.
Inner Ear Morphogenesis: Our work on the wiring of the inner ear has extended naturally to parallel analysis of inner ear morphogenesis. Indeed, inner ear function depends critically on its three-dimensional structure, with three semicircular canals oriented with the three dimensions of space and a coiled cochlea specialized for the detection of wavelengths of sound. Through a forward genetic screen to identify genes required for hearing and balance in mice, we identified Lrig3, a novel member of the Ig superfamily that is essential for canal formation. We went on to show that the key downstream effector is the axon guidance molecule Netrin1, which in the inner ear appears to play a prominent role in canal morphogenesis. We are currently studying how other Lrig genes contribute to inner ear development, how these proteins function at the cellular level, and how Netrin1 mediates its effects. For these studies, we use a combination of biochemistry, mouse genetics, and chick embryology.
Retinal Circuit Assembly: While the cochlea contains only one primary neuronal population, the eye houses a complex array of neurons that cooperate to mediate our sense of vision. Among the most diverse population of neurons are the amacrine cells, interneurons that vary widely in their morphologies and connectivity. Amacrine cells modulate the flow of visual information from photoreceptors to ganglion cells via dendrites that are restricted to the inner plexiform layer. We have been studying how amacrine cells develop a single dendritic arbor that is oriented towards the inner plexiform layer. We demonstrated that reliable formation of this unipolar morphology depends on the activity of the atypical cadherin Fat3. Ongoing studies are aimed at unraveling the cellular and molecular events that are mediated by Fat3. What ligand activates Fat3? What are the downstream effectors? And what are the cellular events that ensure development of a single apical dendrite? We address these questions using a combination of biochemistry to define the molecular interactions and in vivo manipulations to reveal the cellular consequences, including standard mouse genetics and retinal electroporations.
For a complete listing of publications click here.
Last Update: 11/7/2013