Jeffrey D. Macklis, M.D.
Professor of Stem Cell and Regenerative Biology (Harvard University)
Professor of Neurology and Surgery (Harvard Medical School)
7 Divinity Avenue
Cambridge, MA 02138
Our laboratory is directed toward both 1) understanding the molecular controls over neuron sub-type specification and development in the cerebral cortex, and 2) applying developmental controls toward brain and spinal cord repair—specifically, the cellular repair of complex cerebral cortex and cortical output circuitry (in particular, cortico-spinal motor neuron (CSMN) circuitry that degenerates in ALS and other “upper motor neuron” degenerative diseases, and whose injury is centrally involved in loss of motor function in spinal cord injury).
We focus on neocortical projection neuron development and sub-type specification; neural progenitor / “stem cell” biology; induction of adult neurogenesis (the birth of new neurons from within); and directed neuronal differentiation and development of connectivity via molecular manipulation of neural progenitors within murine neocortex. The same biology informs understanding of neuronal subtype specificity of involvement in human neurodegenerative and developmental diseases, in particular ALS / motor neuron disease, PLS, HSPs, Huntington's disease, autism spectrum disorders, and Rett Syndrome.
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; 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 laboratory 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 permissive environment;
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;
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; and
5) identified combinatorial molecular-genetic programs of transcription factors and cell extrinsic peptides that direct lineage-specific development of corticospinal motor neurons and other cortical projection neurons—the first such molecular development programs for any neuron types 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, and will contribute to efforts both toward prevention of dysgenesis, and toward development of cellular repair strategies employing neural transplantation or manipulation of endogenous neural precursors /stem cells in situ.
For a complete listing of publications click here.
Last Update: 11/7/2013