RESEARCH

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; 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 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; and 4) demonstrated 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 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 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.

Selected recent publications

Magavi, SS, Leavitt, BR, Macklis, JD (2000) Induction of neurogenesis in the neocortex of adult mice. Nature; 405: 951-955.

Scharff, C, Kirn, JR, Grossman, M, Macklis, JD, Nottebohm, F (2000) Targeted neuronal death affects neuronal replacement and vocal behavior in adult songbirds.  Neuron; 25(2): 256-257.

Shin, JJ, Fricker-Gates, RA, Perez, FA, Leavitt, BR, Zurakowski, D, Macklis, JD (2000) Transplanted neuroblasts differentiate appropriately into projection neurons with correct neurotransmitter and receptor phenotype in neocortex undergoing targeted projection neuron degeneration. J Neurosci.; 20: 7404-7416.

Catapano, LA, Arnold, MW, Perez, FA, Macklis, JD (2001) Specific neurotrophic factors support the survival of cortical projection neurons at distinct stages of development. J Neurosci; 21(22): 8863-8872.

Fricker-Gates RA, Shin JJ, Tai CC, Catapano LA, Macklis JD (2002) Late-stage immature neocortical neurons reconstruct interhemispheric connections and form synaptic contacts with increased efficiency in adult mouse cortex undergoing targeted neurodegeneration. J Neurosci; 22(10):4045-56.

Eyding D, Macklis JD, Neubacher U, Funke K, Worgotter F (2003) Selective elimination of corticogeniculate feedback abolishes the electroencephalogram dependence of primary visual cortical receptive fields and reduces their spatial specificity. J Neurosci; 23(18):7021-33.

Emsley JG*, Arlotta P*, Macklis JD (2004) Star-cross'd neurons: astroglial effects on neural repair in the adult mammalian CNS Trends Neurosci; 27(5):238-40. (*equal contribution).

Catapano LA, Arlotta P, Cage TA, Macklis JD (2004) Stage-specific and opposing roles of BDNF, NT-3 and bFGF in differentiation of purified callosal projection neurons toward cellular repair of complex circuitry. Eur J Neurosci; 19(9):2421-34.

Kishi N, Macklis JD (2004) MECP2 is progressively expressed in post-migratory neurons and is involved in neuronal maturation rather than cell fate decisions. Mol Cell Neurosci; 27(3):306-21.

Chen, J, Magavi, SSP, Macklis, JD (2004) Neurogenesis of corticospinal motor neurons extending spinal projections in adult mice. PNAS; 101 (46): 16357-16362. pdf

Mitchell BD, Macklis JD (2005) Large-scale maintenance of dual projections by callosal and frontal cortical projection neurons in adult mice. J Comp Neurol; 482(1):17-32.

Arlotta, P*, Molyneaux, BJ*, Chen, J, Inoue, J, Kominami, R, Macklis, JD (2005) Neuronal subtype specific genes that control corticospinal motor neuron development in vivo. Neuron; 45: 207-221. (*equal contribution). pdf

Emsley JG, Mitchell BD, Kempermann G, Macklis JD (2005) Adult neurogenesis and repair of the adult CNS with neural progenitors, precursors, and stem cells. Prog Neurobiol; 75(5):321-41.

Arlotta P, Macklis JD (2005) Archeo-cell biology: carbon dating is not just for pots and dinosaurs. Cell; 122(1):4-6.

Molyneaux, BJ*, Arlotta, P*, Hirata, T, Hibi, M, Macklis, JD (2005) Fezl is required for the birth and specification of corticospinal motor neurons. Neuron; 47: 817-831. (*equal contribution). pdf

Magavi, SSP, Mitchell, BD, Szentirmai, O, Carter, BS, Macklis, JD (2005) Adult-born and pre-existing olfactory granule neurons undergo distinct experience-dependent modifications of their olfactory responses in vivo. J Neurosci; 25(46): 10729-10739. pdf

Steele, AD*, Emsley, JG*, Özdinler, PH, Lindquist, S‡, Macklis, JD‡ (2006) Prion protein (PrPc) positively regulates neural precursor proliferation during developmental and adult mammalian neurogenesis.  PNAS; 103(9):3416-21. (*equal contribution, ‡co-senior author). pdf

Sohur, U.S.*, Emsley, J.G.*, Mitchell, B.D., Kempermann, G., and Macklis, J.D. (2006) Adult neurogenesis and cellular brain repair with neural progenitors, precursors, and stem cells. In “The regenerating brain: a recapitulation of development?” Editors: G. Cook, J. Fawcett, R. Keynes, and M. Tessier-Lavigne Special Issue of Philosophical Transactions of the Royal Society (B) 361: 1477-1497. (*equal contribution).

Özdinler, PH, Macklis, JD (2006) IGF-I specifically enhances axon outgrowth of corticospinal motor neurons. Nat. Neurosci.(11):1371-81. pdf

Emsley, J.G., Macklis, J.D. 2006. "Astroglial heterogeneity closely reflects the neuronal-defined anatomy of the adult murine CNS." Neuron Glia Biol. 2(3):175-86.

Molyneaux, B.J.*, Arlotta, P.*, Menezes, J.R.L., Macklis, J.D. 2007. "Neuronal subtype specification in the cerebral cortex." Nat. Rev. Neurosci. 8(6): 427-37. (*equally contributing first authors). pdf

Breunig, J.J. , Arellano, J.I., Macklis, J.D., Rakic, P. 2007. "Everything that glitters isn't gold: a critical review of postnatal neural precursor analyses." Cell Stem Cell. 1(6):612-27.

Arlotta, P.*, Molyneaux, B.J.*, Jabaudon, D., Yoshida, Y., Macklis, J.D. 2008. "Ctip2 Controls the Differentiation of Medium Spiny Neurons and the Establishment of the Cellular Architecture of the Striatum." J. Neurosci 28(3): 622-632. (*equally contributing first authors). pdf

Lai, T.*, Jabaudon, D.*, Molyneaux, B.J.‡, Azim, E.‡, Arlotta, P., Menezes, J.R.L., Macklis, J.D. 2008. "SOX5 Controls the Sequential Generation of Distinct Corticofugal Neuron Subtypes." Neuron 57: 232-247. (*equally contributing first authors, ‡equally contributing second authors). pdf

Pubmed publication list