A scientific collaborative established to fulfill the promise of stem cell biology.
Jeffrey D. Macklis, MD, D.HST
Affiliation: Massachusetts General Hospital
Molecular controls over projection neuron development; Cellular repair of neocortical circuitry; Adult neurogenesis; Neural stem cell biology
Our laboratory has the long-term aim of brain and spinal cord repairs pecifically, the cellular repair of degenerated or injured complex cerebral cortex and cortical output circuitry (including corticospinal motor neuron circuitry central to ALS and spinal cord injury). Our lab focuses on neural stem cell / precursor biology, molecular development of key cortical neuron lineages (including corticospinal motor neurons), induction of adult neurogenesis (the birth of new neurons from within), and directed neuronal differentiation and development of connectivity via molecular manipulation of neural precursors / stemcells within mouse neocortex.
Toward this goal, and toward the basic goal of understanding neocortical neuronal development, we have five closely related, major research interests: 1) cellular repair of complex CNS circuitry, in particular neocortical and cortical output (e.g. corticospinal, cortico-brainstem) circuitry; 2) induction of neurogenesis (birth of new neurons) from endogenous neural precursors / stem cells; 3) neural precursor / stem cell biology, lineage-specific neuronal differentiation in particular; 4) lineage-specific neuronal differentiation during neocortical development; 5) function of and controls over adult-born neurons in regions of constitutive adult mammalian neurogenesis.
Results from our lab over the past several years: 1)indicate that signals directing neuronal migration and specific differentiation of immature neurons and precursors / stem cells in neocortex can be re-expressed in adult mammals well beyond the period of corticogenesis (development of the neocortex); 2) demonstrated for the first time that reconstruction of even highly complex cortical circuitry is possible, if appropriate immature neurons or precursors / stem cells are provided a correct combination of instructive signals within an appropriately permissiveenvironment; 3) showed for the first time that it is possible via a specific sequence and combination of molecular signals to induce neurogenesis, the birth of new neurons, de novo in the adult mouse neocortex, by activating endogenous precursors in situ,without transplantation; and 4) demonstrated for the first time that newly recruited and integrated neurons are capable of forming complex and behaviorally functional connections by intercalating within existing neuronal networks. Most recently, our laboratory has 5) developed the first successful approaches to isolate, FACS purify (to >99% purity), and culture desired lineages of projection neurons at distinct developmental stages for analysis of lineage-specific controls over survival and differentiation(cortical inter-hemispheric callosal neurons and corticospinal motor neurons, in particular); and 6) identified combinatorial programs of transcription factors / gene expression that direct lineage-specific development of corticospinal motor neurons and other lineagesthe first such molecular development programs for any neuron type in the brain. Elucidating the molecular mechanisms allowing directed, lineage-specific neuronal differentiation, repopulation, and circuit repair is the focus of substantial effort in the lab.
Bio-Sketch
Jeffrey D. Macklis laboratory is directed toward the cellular repair of brain and spinal cord circuitry, specifically complex cerebral cortex and cortical output circuitry (including cortico-spinal motor neuron circuitry). The lab focuses on neural precursor / stem cell biology, neocortical projection neuron differentiation, functional neuronal circuit repair via transplantation, and induction of neurogenesis by molecular manipulation of endogenous neural precursors / stem cells within murine neocortex. Since 2003, he has been Director of the newly established Massachusetts General Hospital-Harvard Medical School (MGH-HMS) Center for Nervous System Repair (CNSR). He is also Program Head, Neuroscience, Harvard Stem Cell Institute, Harvard University; and Co-Director for the Regeneration and Repair Program of the Harvard Center for Neurodegeneration and Repair. He attended M.I.T., HMS, and graduate school at M.I.T. within the Harvard-M.I.T. Division of Health Sciences and Technology (HST). He was a postdoctoral fellow in developmental neuroscience with Richard Sidman at HMS. He trained clinically in Internal Medicine at Brigham and Women's Hospital/HMS and in adult neurology in the Harvard-Longwood Neurological Training Program. Until moving to MGH in 2003 to establish the new MGH-HMS CNSR, he was in the basic science Division of Neuroscience at Children's Hospital, and was Co-Director of the Parkinson's Disease and Related Disorders Program at Brigham and Womens Hospital.
Dr. Macklis is the recipient of a number of awards and honors, including a Rita Allen Foundation Scholar Award, an Innovation Award from the NIH Directors Office, a Soderberg Prize Symposium Lectureship at the Swedish Society for Medicine, The CNS Foundation Award, and a Senator Jacob Javits Award in the Neurosciences from the NINDS/NIH.
