Our primary focus is to understand the mechanisms underlying the mammalian central nervous system development. In particular, we are interested in understanding mechanisms of polarized signaling that regulate the proliferation and placement of neuronal progenitors in the developing cerebral cortex and whether similar cellular processes assist in neurons faithful ability to acquire unique yet often complex polarized morphologies.
To approach these questions, we combine mouse genetics, in uterus embryonic manipulation, and ex vivo preparations (e.g. hippocampal dissociated neuronal culture, organotypic brain slice culture) with various assays including two-photon/confocal laser scanning microscopy imaging. Employing these techniques, we hope to gain better understanding of the mechanism required for the polarized spatial restriction of critical signaling complexes in neural progenitors of the developing cerebral cortex, advancing our knowledge of neural stem cell biology and aiding in the future treatment of neural developmental disorders and neurodegenerative diseases.
Current lab projects:
I. CRMP2: A key regulatory mediator of neuropsychiatric disorders
During development of the mammalian nervous system, polarized signaling mechanisms regulate neuronal cell division, migration, and differentiation into mature, functional circuits. Understanding the complex mechanisms that regulate each of these processes can provide valuable insight into our understanding and treatment of neurodevelopmental disorders. Specifically, mechanisms that orchestrate axonal polarization, specification, outgrowth, and guidance remain at the forefront of our study of neural development and axonal regeneration. CRMP2 is crucial for axon-dendritic specification and axonal extension in the developing brain and contributes to regeneration/degeneration in the mature brain. Many of the activities of CRMP2 are mediated through its ability to promote microtubule assembly via physical interaction with tubulin heterodimers and the Sra-1/WAVE1–actin complex. CRMP2-mediated axonal growth is facilitated through an interaction with Numb, allowing endocytosis of specific molecules such as the neuronal adhesion molecule L1 at the growth cone. Furthermore, CRMP-2’s ability to specify axon/dendrite fate and regulate cargo transport during axonal growth/regeneration has been shown to be facilitated and/or antagonized through a complex network of alternative protein-protein interactions, including kinesin-1 light chain, dynein, chimaerin, phospholipase D, calmodulin, neurofibromin, CaV2.2, and, more recently, the neuronal ceroid lipofuscinosis protein, CLN6. In this study, we focus on this novel interaction with CLN6, exploring how it may provide a unique mechanism for localized CRMP-2 signaling and how disruption in this interaction could facilitate a loss in many CRMP-2-dependent processes.
II. MARCKS-associated signaling complexes in cortical development
Radial glia (RG) function as a source of new neurons and provide an instructive scaffold for neuronal migration in the developing neocortex. With a cell soma in the ventricular zone, an elongated radial process, and specialized adhesive contacts with both ventricular and pial surfaces, it is of paramount importance to RG function that they tightly regulated cell polarity. In this study we investigate signaling complexes critical for the proper polarized proliferation and differentiation of neural progenitors in the developing cerebral cortex. Recently we have shown that the myristoylated alanine-rich C-kinase substrate protein (MARCKS) modulates RG proliferation and placement by potentially serving as an anchor of spatially restricted polarity signaling complexes. We believe that the membrane-targeting of MARCKS anchors polarized signaling complexes essential for apico-basal polarity, facilitating appropriate proliferation and differentiations of neural progenitors in the developing cerebral cortex. Building on this hypothesis, our works seeks to identify key interacting partners and regulators of the MARCKS-associated signaling complex and understand how modulating in this complex affects cortical development.
Contact Information for Weimer Lab:
Jill Weimer, PhD
Associate Scientist, Sanford Children’s Health Research Center
Assistant Professor, Department of Pediatrics
Sanford School of Medicine of the University of South Dakota
Sanford Research Center, Room 2240
2301 E 60th Street N
Sioux Falls, SD 57104