Jeffrey D. Macklis, M.D., Ph.D.
Jeffrey D. Macklis’ laboratory is directed toward both 1) understanding molecular controls and mechanisms over neuron subtype specification, development, diversity, axon guidancecircuit formation, and pathology in the cerebral cortex (e.g. of corticospinal motor neurons – CSMN – central in motor neuron disease / ALS and spinal cord injury, or callosal projection neurons – CPN – in autism spectrum disorders and intellectual disability), and 2) applying developmental controls toward both brain and spinal cord regeneration and directed differentiation for in vitro therapeutic and mechanistic screening. The lab focuses on neocortical projection neuron development and subtype specification; neural progenitor / “stem cell” biology; induction of adult neurogenesis (birth of new neurons); subtype-specific growth cone biology; and directed neuronal subtype differentiation via molecular manipulation of neural progenitors and pluripotent cells (ES/iPS). The same biology informs understanding of neuronal specificity of vulnerability in human diseases. Macklis is the Max and Anne Wien Professor of Life Sciences, and Professor of Stem Cell and Regenerative Biology, in the Department of Stem Cell and Regenerative Biology, and Center for Brain Science, Harvard University. He is also Professor of Neurology [Neuroscience] at Harvard Medical School (HMS); Executive Committee member of the Harvard Stem Cell Institute (HSCI); former founding Program Head, Neuroscience / Nervous System Diseases, HSCI; former founding Director of the MGH-HMS Center for Nervous System Repair. He is a member of the Harvard University graduate Programs in Neuroscience (PiN); Developmental and Regenerative Biology (DRB); Biological and Biomedical Sciences (BBS); and Molecules, Cells, and Organisms (MCO); Harvard-M.I.T. M.D.-Ph.D. Program; and of the affiliated faculty of the HarvardM.I.T. Division of Health Sciences and Technology (HST), and of M.I.T. within HST. He attended M.I.T. (S.B. Bioelectrical Engineering; S.B. Literature-Philosophy), Harvard Medical School (Harvard-M.I.T. HST Program), and graduate school at M.I.T. within HST, a graduate student with Richard L. Sidman. He was a postdoctoral fellow in developmental neuroscience with Richard Sidman at HMS, where he also trained clinically in Internal Medicine at Brigham and Women’s Hospital (BWH) and adult neurology in the Harvard Neurological Training Program. He is no longer clinically active. He assumed his current position at Harvard University in Cambridge in 2007, and moved his lab physically to Cambridge in 2011. Macklis is the recipient of a number of awards and honors. He is an Allen Distinguished Investigator of the Paul G. Allen Frontiers Group, a Brain Research Foundation Fellow, and the recipient of a 2017 NIH Director’s Pioneer Award. Prior honors include a Rita Allen Foundation Scholar Award, a Director’s Innovation Award from the NIH Director’s Office, a Senator Jacob Javits Award in the Neurosciences and MERIT Award from the NINDS/NIH. the CNS Foundation Award, the Cajal-Krieg Cortical Discoverer Prize, numerous honorary and named institutional lectureships and visiting professorships (e.g. Leonardo da Vinci, Raine, Moon, Grass, Stellar, Sherman), and several Hoopes Prizes for excellence in undergraduate research mentoring.
Toward Elucidating Neuronal Subtype-Specific Subcellular Vulnerability in ALS
This talk will discuss two central ideas relevant to ALS, both dealing with circuit development, synaptic maintenance, and selective vulnerability of the “upper motor neurons” involved: 1) that distinct and subcellularly localized molecular machinery of corticospinal motor neurons (CSMN) and their related subsets of subcerebral projection neurons (SCPN), and potentially shared molecular components or pathways with spinal motor neurons (SMN), underlie the selective and specific vulnerability of these circuit partners among all the other thousands of relatively unaffected neuronal populations; and 2) that even subtle abnormalities in the development, synaptic maintenance, and subcellular molecular machinery of CSMN / SCPN (and SMN, for that matter) might both be explained by specific functions of many/most of the known ALS vulnerability genes, and predispose these specific cortical neuron populations to vulnerability and later neurodegeneration in ALS / MND.
Given the immense diversity of CNS neuronal subtypes (cortical projection neurons in particular), and the complexity of their connections, complex and subtype-specific subcellular molecular machinery (in particular, in growth cones during circuit development, which mature into diverse and potentially quite subtype-specific forms of synapses) regulate differentiation, circuit connectivity, synapse function, and ultimately survival. This subcellular and subtype- / stage-specific in vivo molecular machinery was previously experimentally inaccessible.
We recently developed experimental and analytic approaches to deeply investigate subtype- and stage-specific subcellular RNA and protein molecular machinery directly in vivo in mice (and very recently with human neurons), in particular in growth cones vs. their own parent somata (Poulopoulos*, Murphy*, Nature, 2019). We have discovered a number of novel and in some cases non-canonical modes of subtype-specific subcellular RNA processing, localization, and utilization, functions of a number of ALS vulnerability genes. During circuit development and function, even very subtle errors might be introduced that anticipate later degeneration of specifically vulnerable neuronal populations. I will discuss our initial work on these issues.