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Jeffrey D. Macklis, M.D.

Professor of Surgery and Neurology

Massachusetts General Hospital

Center for Nervous System Repair, EDR 410
55 Fruit St
Boston, MA 02114
Telephone: 617-724-0678
Fax: 617- 726-2310
Email: jeffrey_macklis@hms.harvard.edu
Lab Website: The Macklis Lab

Our laboratory has the long-term aim of brain and spinal cord repair—specifically, 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 / stem cells 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 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.
  5. Most recently, our laboratory has 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)
  6. Identified combinatorial programs of transcription factors / gene expression that direct lineage-specific development of corticospinal motor neurons and other lineages—the 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.

References:

  • Arlotta P, Molyneaux BJ, Chen J, Inoue J, Kominami R, Macklis J.D.  (2005)  Neuronal subtype specific genes that control corticospinal motor neuron development in vivo.  Neuron 45:207-221 (with cover).
  • Ozdinler PH, Macklis JD (2006) IGF-I specifically enhances axon outgrowth of corticospinal motor neurons.  Nature Neuroscience 9(11):1371-1381.
  • Molyneaux BJ, Arlotta P, Menezes J, Macklis JD. (2007) Neuronal subtype specification in the cerebral cortex.  Nature Reviews Neuroscience 8:427-437.
  • Lai T*, Jabaudon D*, Molyneaux BJ#, Azim E#, Arlotta P, Menezes J, Macklis JD.  (2008).  Sox5 controls the sequential generation of distinct corticofugal neuron subtypes.  Neuron 57:232-247.
  • Joshi P*, Molyneaux BJ, Feng L, Xie X, Macklis JD#, Gan L#.  (2008)  Bhlhb5 regulates the post-mitotic acquisition of area identities in layers II-V of the developing neocortex.  Neuron 60:258-272.
  • Azim E, Jabaudon D, Fame R, Macklis JD.  (2009) Sox6 controls dorsal-ventral progenitor parcellation and interneuron diversity during development of the neocortex.  Nature Neuroscience.

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