[1] In 2002, he moved to Massachusetts General Hospital (MGH), where he was the founding Director of the MGH-HMS Center for Nervous System Repair (2002–2011), and Professor of Neurology [Neuroscience].
The Macklis laboratory is directed toward both 1) understanding molecular controls and mechanisms over neuron subtype development neural development, diversity, axon guidance-circuit formation-growth cone biology, and degeneration-disease in the cerebral cortex cerebral cortex[e.g. corticospinal neurons (CSN) in motor neuron disease (ALS, HSPs, PLS), and associative circuitry in autism (ASD) and intellectual disability], and 2) applying developmental controls toward both brain and spinal cord regeneration and developmentally-directed adult neurogenesis[e.g. CSN circuitry that degenerates in ALS-MND, and whose injury is central to loss of motor function in spinal cord injury] and directed differentiation for in vitro mechanistic modeling using human assembloids.
Macklis developed an approach of noninvasive, optically-biophysically-targeted, population-specific apoptotic neuronal degeneration, via exogenous long-wavelength chromophore targeting to specific populations by retrograde transport.
This enabled investigation of transplantation of developmentally primed and appropriate immature neurons, with integration into new synaptic space, mimicking adult neurogenesis in dentate gyrus and olfactory bulb.
They were first to manipulate endogenous neural progenitors/precursors/“stem cells” in situ (adult mouse) to undergo induced neurogenesis in “non-neurogenic” cortex; demonstrated that newborn neurons progressively migrate, differentiate layer- and region-specifically, and some extend appropriate long-distance projections, with re-formation de novo of targeted, degenerated circuitry in adult mouse cortex to thalamus and spinal cord.
The lab published the first identification of function of adult-born mouse neurons (in olfactory bulb)– they uniquely provide a form of synaptic plasticity at cellular level, undergoing response enhancement to novel odorant stimuli (experience-dependent modification) during a critical period, implicating them in olfactory learning, not simply as “replacement cells”.
In a linked set of major contributions, the Macklis lab first invented and developed now widely-used approaches to isolate, protect, and FACS purify healthy mouse cortical projection neurons of multiple subtypes at developmentally distinct critical stages, uniquely enabling investigation of subtype- and stage-specific controls over survival, differentiation, axon growth, circuitry formation.
This FACS-based neuronal purification for transcriptional analysis of small homogeneous samples of multiple subtypes of projection neurons at critical developmental stages enabled addressing major questions re: dynamic and combinatorially interacting molecular developmental controls over subtype-specific development/diversity of distinct subtypes.
Early in this work, the lab identified and functionally investigated Ctip2/Bcl11b, Fezl/Fezf2, Sox5, Bhlhb5, Lmo4, RORb, Sox6, Ctip1/Bcl11a, Fog2, and a number of other widely known controls over neuron subtype and area specification in mammalian cerebral cortex.
Together, the work has contributed to understanding development, organization, function, and evolution of cortical circuitry, and toward directed differentiation of progenitors or ES/iPS, regeneration, reprogramming, induced neurogenesis, and identification of disease genes.
They invented subtype-specific fluorescent small particle sorting (FSPS), building on the lab's early development of neuronal FACS.