Jeffrey D. Macklis is an American neuroscientist. He is the Max and Anne Wien Professor of Life Sciences in the Department of Stem Cell and Regenerative Biology and Center for Brain Science at Harvard University, Professor of Neurology [Neuroscience] at Harvard Medical School, and on the Executive Committee and a Member of the Principal Faculty of the Neuroscience / Nervous System Diseases Program at the Harvard Stem Cell Institute. [1]
Macklis received two S.B. degrees in bioelectrical engineering and in literature/philosophy from the Massachusetts Institute of Technology. [1] He received his M.D. and D.Sc.Tech. in 1984 from Harvard Medical School (HMS) and the Harvard–MIT Division of Health Sciences and Technology (HST); his graduate school advisor was Prof. Richard L. Sidman. [2] He later completed a postdoctoral fellowship in developmental neuroscience with Sidman. Macklis trained clinically in internal medicine at Brigham and Women’s Hospital (BWH) and in adult neurology in the Harvard-Longwood Neurological Training Program. [1] , then pursued a largely 90% laboratory / 10% clinical career specializing in Parkinson's disease-related neurodegenerative disorders and adolescent-young adult neurology in his earlier years. He has not been clinically active since 2002.
Macklis first established his laboratory[ when? ] in the Basic Science Division of Neuroscience of Boston Children's Hospital (BCH) [now Kirby Center]. He also co-directed the Parkinson's Disease and Related Disorders Program at BWH. [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].
In 2004, Macklis was the founding Program Head of the Neuroscience / Nervous System Diseases Program at the Harvard Stem Cell Institute at Harvard University, which he directed until 2013. [3]
In 2007, Macklis was appointed Professor of Stem Cell and Regenerative Biology at Harvard University, in both the Faculty of Arts and Sciences and Harvard Medical School, physically based on the main Harvard University campus in Cambridge, Massachusetts. In 2014, He was appointed the Max and Anne Wien Professor of Life Sciences, Harvard University, in the department of Stem Cell and Regenerative Biology, and Center for Brain Science. He is a faculty member of the Harvard graduate programs in Neuroscience; [4] Biological and Biomedical Sciences; [5] Developmental and Regenerative Biology; and Molecules, Cells, and Organisms; The Harvard-M.I.T. M.D.-Ph.D. Program; and the Harvard-MIT Division of Health Sciences and Technology [1]
Macklis was awarded a Kleberg Foundation predoctoral fellowship, a Leopold Schepp Foundation Scholarship, and an NIH K08 transition to independence award. He was a Rita Allen Foundation Scholar. He was awarded an NIH Director's Innovation Award. He was awarded a Jacob Javits Award in the Neurosciences and MERIT Award from NINDS in 2004. Macklis became a Brain Research Foundation Fellow in 2015, and an Allen Distinguished Investigator of the Paul G. Allen Frontiers Group in 2015. [6] He became a Simons Foundation Autism Research Initiative (SFARI) investigator in 2017. [7] He was awarded an NIH Director's Pioneer Award in 2017. [8] He was named an Oxford Martin School Visiting Fellow at University of Oxford and St. John's College, and a Plumer Fellow at St. Anne's College 2022-2023.
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.
The lab focuses on neocortical projection neuron development and subtype specification in mice and human neuron models; new approaches to subtype-specific axonal growth cone biology; neural progenitor / “stem cell” biology; induction of adult neurogenesis (the birth of new neurons); and directed neuronal subtype differentiation and core long-distance circuit formation via molecular manipulation of endogenous neural progenitors and pluripotent cells (ES/iPS). The same biology informs understanding of neuronal specificity of vulnerability in human neurodegenerative and developmental diseases. Relationships and application of cortical development to evolution, disease, and regeneration are frequent themes. [9] https://macklislab.hscrb.harvard.edu/
The Macklis laboratory has made major contributions to several areas and neuroscience fields. A central contribution of the lab’s early work was in the area of cellular CNS / neocortical circuit repair by transplantation of immature neocortical neurons and neural precursors. In the CNS repair field before, there was focus on tissue block “grafts” or heterotopic cells without neuronal migration or integration, with assumption that integration in post-development CNS (cortex especially) was not possible. 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.
In 2000, the Macklis lab published the first two reports of “induction of neurogenesis”, a contribution that is credited with starting this new subfield. 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. In collaborative work, the lab induced behaviorally functional neurogenesis in situ in zebrafinch from endogenous progenitors. 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 was previously thought impossible, due to neuronal axotomy/dendritotomy. The lab employed this neuronal FACS first for studies of subtype-specific cell biology and context-specific peptide growth factor regulation of diverse projection neurons.
They then identified a set of combinatorially and sequentially interacting molecular controls (largely transcriptional regulators) that direct subtype-specific specification, development, and diversity of projection neurons (in particular, corticospinal, callosal, corticothalamic, corticostriatal, and diverse sub-subtypes with unique circuitry). 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.
Later portions of this work opened up new thinking in cortical development and regenerative reprogramming, with the first reports of postmitotic regulation of neuronal identity, then of acquisition of precise areal identity, then target-specific axon outgrowth and multi-projection connectivity. This is in contrast to previous views that neuronal differentiation was decided by progenitors just before giving rise to postmitotic neurons. The lab has put forward a theoretical model of a multi-stage, nested "Boolean" “molecular logic” of progenitor- and post-mitotic, areally specific, combinatorial molecular controls over precise development of key cortical and other forebrain projection neuron types. 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.
More recently, the Macklis lab pioneered subcellular molecular investigation of immensely polarized projection neurons (length 103-105 X soma diameter) and their local TF-regulated growth cone and synapse RNA and protein molecular machinery that implements subtype-, circuit-specific brain “wiring” and unique cell biology, then functions in developing synapses, likely in synapse maintenance, function, and dysfunction. They invented subtype-specific fluorescent small particle sorting (FSPS), building on the lab's early development of neuronal FACS. They developed new experimental and analytic approaches for quantitative, comprehensive, high-throughput “subcellular RNA-proteome mapping”, & ultra-low-input proteomics, and nanoRibo-seq for investigation of subcellular translational regulation.
The cerebral cortex, also known as the cerebral mantle, is the outer layer of neural tissue of the cerebrum of the brain in humans and other mammals. The cerebral cortex mostly consists of the six-layered neocortex, with just 10% consisting of allocortex. It is separated into two cortices, by the longitudinal fissure that divides the cerebrum into the left and right cerebral hemispheres. The two hemispheres are joined beneath the cortex by the corpus callosum. The cerebral cortex is the largest site of neural integration in the central nervous system. It plays a key role in attention, perception, awareness, thought, memory, language, and consciousness. The cerebral cortex is part of the brain responsible for cognition.
The development of the nervous system, or neural development (neurodevelopment), refers to the processes that generate, shape, and reshape the nervous system of animals, from the earliest stages of embryonic development to adulthood. The field of neural development draws on both neuroscience and developmental biology to describe and provide insight into the cellular and molecular mechanisms by which complex nervous systems develop, from nematodes and fruit flies to mammals.
In vertebrates, a neuroblast or primitive nerve cell is a postmitotic cell that does not divide further, and which will develop into a neuron after a migration phase. In invertebrates such as Drosophila, neuroblasts are neural progenitor cells which divide asymmetrically to produce a neuroblast, and a daughter cell of varying potency depending on the type of neuroblast. Vertebrate neuroblasts differentiate from radial glial cells and are committed to becoming neurons. Neural stem cells, which only divide symmetrically to produce more neural stem cells, transition gradually into radial glial cells. Radial glial cells, also called radial glial progenitor cells, divide asymmetrically to produce a neuroblast and another radial glial cell that will re-enter the cell cycle.
Neural stem cells (NSCs) are self-renewing, multipotent cells that firstly generate the radial glial progenitor cells that generate the neurons and glia of the nervous system of all animals during embryonic development. Some neural progenitor stem cells persist in highly restricted regions in the adult vertebrate brain and continue to produce neurons throughout life. Differences in the size of the central nervous system are among the most important distinctions between the species and thus mutations in the genes that regulate the size of the neural stem cell compartment are among the most important drivers of vertebrate evolution.
Radial glial cells, or radial glial progenitor cells (RGPs), are bipolar-shaped progenitor cells that are responsible for producing all of the neurons in the cerebral cortex. RGPs also produce certain lineages of glia, including astrocytes and oligodendrocytes. Their cell bodies (somata) reside in the embryonic ventricular zone, which lies next to the developing ventricular system.
The subventricular zone (SVZ) is a region situated on the outside wall of each lateral ventricle of the vertebrate brain. It is present in both the embryonic and adult brain. In embryonic life, the SVZ refers to a secondary proliferative zone containing neural progenitor cells, which divide to produce neurons in the process of neurogenesis. The primary neural stem cells of the brain and spinal cord, termed radial glial cells, instead reside in the ventricular zone (VZ).
The subgranular zone (SGZ) is a brain region in the hippocampus where adult neurogenesis occurs. The other major site of adult neurogenesis is the subventricular zone (SVZ) in the brain.
Neurogenins are a family of bHLH transcription factors involved in specifying neuronal differentiation. It is one of many gene families related to the atonal gene in Drosophila. Other positive regulators of neuronal differentiation also expressed during early neural development include NeuroD and ASCL1.
Gyrification is the process of forming the characteristic folds of the cerebral cortex.
Eomesodermin also known as T-box brain protein 2 (Tbr2) is a protein that in humans is encoded by the EOMES gene.
Endogenous regeneration in the brain is the ability of cells to engage in the repair and regeneration process. While the brain has a limited capacity for regeneration, endogenous neural stem cells, as well as numerous pro-regenerative molecules, can participate in replacing and repairing damaged or diseased neurons and glial cells. Another benefit that can be achieved by using endogenous regeneration could be avoiding an immune response from the host.
Corticogenesis is the process during which the cerebral cortex of the brain is formed as part of the development of the nervous system of mammals including its development in humans. The cortex is the outer layer of the brain and is composed of up to six layers. Neurons formed in the ventricular zone migrate to their final locations in one of the six layers of the cortex. The process occurs from embryonic day 10 to 17 in mice and between gestational weeks seven to 18 in humans.
Epigenetic regulation of neurogenesis is the role that epigenetics plays in the regulation of neurogenesis.
Proneural genes encode transcription factors of the basic helix-loop-helix (bHLH) class which are responsible for the development of neuroectodermal progenitor cells. Proneural genes have multiple functions in neural development. They integrate positional information and contribute to the specification of progenitor-cell identity. From the same ectodermal cell types, neural or epidermal cells can develop based on interactions between proneural and neurogenic genes. Neurogenic genes are so called because loss of function mutants show an increase number of developed neural precursors. On the other hand, proneural genes mutants fail to develop neural precursor cells.
A neuronal lineage marker is an endogenous tag that is expressed in different cells along neurogenesis and differentiated cells such as neurons. It allows detection and identification of cells by using different techniques. A neuronal lineage marker can be either DNA, mRNA or RNA expressed in a cell of interest. It can also be a protein tag, as a partial protein, a protein or an epitope that discriminates between different cell types or different states of a common cell. An ideal marker is specific to a given cell type in normal conditions and/or during injury. Cell markers are very valuable tools for examining the function of cells in normal conditions as well as during disease. The discovery of various proteins specific to certain cells led to the production of cell-type-specific antibodies that have been used to identify cells.
In vertebrates, the ventricular zone (VZ) is a transient embryonic layer of tissue containing neural stem cells, principally radial glial cells, of the central nervous system (CNS). The VZ is so named because it lines the ventricular system, which contains cerebrospinal fluid (CSF). The embryonic ventricular system contains growth factors and other nutrients needed for the proper function of neural stem cells. Neurogenesis, or the generation of neurons, occurs in the VZ during embryonic and fetal development as a function of the Notch pathway, and the newborn neurons must migrate substantial distances to their final destination in the developing brain or spinal cord where they will establish neural circuits. A secondary proliferative zone, the subventricular zone (SVZ), lies adjacent to the VZ. In the embryonic cerebral cortex, the SVZ contains intermediate neuronal progenitors that continue to divide into post-mitotic neurons. Through the process of neurogenesis, the parent neural stem cell pool is depleted and the VZ disappears. The balance between the rates of stem cell proliferation and neurogenesis changes during development, and species from mouse to human show large differences in the number of cell cycles, cell cycle length, and other parameters, which is thought to give rise to the large diversity in brain size and structure.
Neurogenesis is the process by which nervous system cells, the neurons, are produced by neural stem cells (NSCs). It occurs in all species of animals except the porifera (sponges) and placozoans. Types of NSCs include neuroepithelial cells (NECs), radial glial cells (RGCs), basal progenitors (BPs), intermediate neuronal precursors (INPs), subventricular zone astrocytes, and subgranular zone radial astrocytes, among others.
The Radial Unit Hypothesis (RUH) is a conceptual theory of cerebral cortex development, first described by Pasko Rakic. The RUH states that the cerebral cortex develops during embryogenesis as an array of interacting cortical columns, or 'radial units', each of which originates from a transient stem cell layer called the ventricular zone, which contains neural stem cells known as radial glial cells.
Intermediate progenitor cells (IPCs) are a type of progenitor cell in the developing cerebral cortex. They are multipolar cells produced by radial glial cells who have undergone asymmetric division. IPCs can produce neuron cells via neurogenesis and are responsible for ensuring the proper quantity of cortical neurons are produced. In mammals, neural stem cells are the primary progenitors during embryogenesis whereas intermediate progenitor cells are the secondary progenitors.
Paola Arlotta is the Golub Family Professor of Stem Cell and Regenerative Biology at Harvard University and chair of the Harvard Stem Cell and Regenerative Biology (HSCRB). Her research focuses on the development of neuron types in the cerebral cortex. She is best known for her work using 3D cerebral organoids derived from human induced pluripotent stem cells (iPSCs) to study cortical development in neurodegenerative and neuropsychiatric disorders.