Paola Arlotta


Paola Arlotta is an Italian molecular biologist and neuroscientist who is a Professor and Chair of the Stem Cell and Regenerative Biology Department at Harvard University. Arlotta leads the neuroscience program within the Harvard Stem Cell Institute and is a member of Stanley Center for Psychiatric Research within the Broad Institute. Arlotta's research focuses on understanding the genetic and molecular mechanisms underlying development of the brain's cerebral cortex, such that she can apply this knowledge to regenerate the brain in disease states.

Early life and education

Arlotta grew up in Northern Italy, where her family was active in a variety of winter sports. Arlotta was passionate about science from a young age, and said she 'can't remember a time when was not interested in Biology'. Her interest became more serious in high school, when her science teacher provided the opportunity for scientific experimentation and fostered an approach to scientific inquiry that required deep thinking and understanding. Arlotta decided to pursue her undergraduate degree in Biological Science and then her Masters in Biochemistry from the University of Trieste in Italy. For her Masters thesis, Arlotta studied the regulation of homeodomain containing proteins by the high mobility group I family of molecular proteins. She found that HMGI proteins are able to interfere with the binding of homeodomains to their target genes a method of controlling transcription and thus cell differentiation and development.
Arlotta pursued a graduate degree in Molecular Biology from the University of Portsmouth in the UK. She worked under the mentorship of Santa Jeremy Ono at the Schepens Eye Research Institute within the Brigham and Women's Hospital at Harvard University Medical School. During her PhD studies, Arlotta continued to explore transcriptional regulation through HMG I proteins. Arlotta completed her PhD in 2000 and then began her postdoctoral training under the mentorship of Jeffrey Macklis at Harvard Medical School. She worked in both Boston Children's Hospital and Massachusetts General Hospital studying neurogenesis and CNS repair. Arlotta was also an instructor in Neurosurgery at Harvard Medical School until 2007.

Regulation of Transcription

In her graduate work, Arlotta continued to probe the biological role of HMG I proteins and binding sites in transcriptional regulation and homeostasis. Arlotta and her colleagues developed a mouse mode to explore the role of HMG I-C in the development of benign fat tumors known as lipomas. They found that, even when the DNA binding sites for HMG I-C are present, when the HMG I-C protein is truncated, it leads to development of lipidomas. Their work helped to create a mouse model to explore the development and biology of benign tumorigensis. Arlotta then studied another DNA binding protein NFX.1 and elucidated its possible biological roles beyond regulation of class II MHC gene expression.

Neural Cell Type Differentiation

In the beginning of her postdoctoral work, Arlotta explored the neural stem cell niches in the brain that refute prior hypotheses that the CNS is incapable of regenerating new neurons. The promise of exploring the biology of these niches lies in the ability to intrinsically stimulate neurogenesis during or after disease to repair dysfunctional brain processes. Arlotta and her colleagues then dedicated their time to understanding the mechanisms underlying the specification and differentiation of neurons to understand how one might harness neural stem cells and siphon them towards specific subpopulations that may have been affected in disease. Arlotta and her colleagues first explored corticospinal motor neuron specification and development. They found specific genes, that via combinatorial expression, are important in the development of CSMNs. Further, CSMN neurons are implicated in the degenerative processes of ALS, so Arlotta's work provides critical genetic insights into the population of neurons that could be targeted in ALS treatment and neural regeneration. Arlotta and her colleagues then found that Ctip2 is an important regulator of medium spiny neuron differentiation as, in Ctip2 knockouts, MSNs fail to differentiate and have reduced expression of typical MSN markers. Since MSN dysfunction is a contributing factor to Huntington's disease, Arlotta's postdoctoral work, yet again, helped to elucidate a disease relevant neural subtype, which could be targeted for development and specification to help to prevent CNS disease.

Career and research

In 2007, Arlotta joined the faculty at Harvard University. She became the Morris Kahn Associate Professor of Stem Cell and Regenerative Biology as well as a Faculty at the Harvard Stem Cell Institute. In 2008, Arlotta received a Seed grant, followed by her first R01, which boosted the beginnings of a successful independent career. In 2014, Arlotta went up for tenure and soon after she became the Golub Family Professor of Stem Cell and Regenerative Biology at Harvard. In 2018, Arlotta was appointed the Chair of the Stem Cell Biology and was appointed to the Quantitative Biology Executive Council.
As the principal investigator of her lab, Arlotta's research program centers around understanding brain development and neural regeneration. By exploring how cells in the brain develop their distinct identities in the cerebral cortex, Arlotta is setting the foundation to be able to target these genetic and molecular processes to repair the brain in disease states. Arlotta is also an Editor for the Journal Development and an advocate for women in STEM. Arlotta and a group of scientists wrote an article listing seven strategies to achieve equity and inclusion in science, technology, engineering, and mathematics fields.

Exploring Differentiation of Neurons in the CNS and in Brain Organoids

Early into her faculty career, Arlotta made a critical discovery, that corticofugal projection neurons specifically differentiated in the presence of a single transcription factor Fezf2. When Arlotta and Caroline Rouaux injected Fezf2 vectors in the striatum, they were able to induce expression of CFu neurons in the striatum, even though these neurons are normally expressed in the cortex. Their discovery highlighted the potential of pre-destined GABAergic MSN's to change fate to CFU neurons under the influence of a single transcription factor, Fezf2. These findings jostled the field of neuroscience by showing that pre-destined neurons can in fact change fate, even in vivo. The idea of reprogramming neural fate has the potential to revolutionize the disease treatment in the future. Continuing to explore developmental neural programs in cells, Arlotta explored the effects on cortical development in the absence of Fezf2. Absence of Fezf2 caused alterations in inhibitory neuron development, but it appeared that presence of nearby projection neurons was sufficient to guide inhibitory interneuron recruitment. These findings highlighted the novel role of projection neurons in guiding the laminar fate of cortical interneurons.
In 2013, Arlotta and Rouaux showed that they could reprogram neurons post-mitotically. Arlotta and Rouaux show that exposure to Fezf2 can reprogram post-mitotic callosal neurons to become layer V/VI CFu neurons during a specific post-mitotic developmental window. This work was followed up by Zhanlei Ye and Mohammed Mostajo-Radji who showed that afferent inhibitory synapses from parvalbumin-positive interneurons could be rewired upon pyramidal neuron reprogramming. Arlotta and her team then found that Fezf2 directly activates the glutamatergic properties of CSMNs and inhibits Gad1, which would promote GABAergic neural identity.
In 2011, Arlotta and her colleagues, including her postdoctoral fellow and lead author Feng Zhang, who was the first to apply CRISPR to mammalian systems, developed a novel genetic tool for targeting transcription factors to specific genetics sites. They called their technology TALEs, derived from a plant pathogen. TALEs typically modulate gene expression, but Arlotta and her colleagues engineered 17 different TALEs to bind to bind to various DNA loci to stimulate transcription. They further showed that these TALEs could be used to modulate transcription in mammalian cells.
Arlotta and her trainee Giulio Srubek Tomassy at Harvard then made a finding about myelin, the insulation around neurons that allows them to pass signals over long distances. They first observed that myelination was not an all or none process, but rather a seemingly regulated and specific process depending on neural identity and environment. Using electron microscopy, Arlotta and her team found that myelination was quite diverse in the neocortex, such that stretches of unmyelinated axon would follow significantly myelinated axon. They found myelination to be a characteristics of each neural subtype reflecting random interaction between neurons and oligodendrocytes, myelinating cells of the CNS. Arlotta and her team propose that this diversity and stochasticity of myelination underlies the diverse array of communication patterns that arise in the cortex.
Arlotta also develops and applies brain organoids to test various aspects of brain development and neurogenesis in models that better recapitulate the CNS but are more malleable to testing. Arlotta led a team of researchers towards developing organoids that were able to grow for up to 9 months, generate dendritic spines, as well as a broad array of diverse cells types as would be observed in the human brain. Arlotta and her colleagues were able to drive the activity of these cells optogenetically, underscoring the potential of this technology to address critical neuroscience questions that are not as easily achieved in the rodent brain. Following this study, Arlotta and her colleagues sought to address the significant variability seen between organoids that inhibits their use in reliable probing of neurobiological mechanisms and disease states. Arlotta and her colleagues developed a model of the dorsal forebrain and conducted RNA sequencing to deduce that developmental trajectories and cell types displayed similar variability to endogenous brains. Overall, their study showed that development can be reproducible modelled in brain organoids and these pose a highly useful took for further probing of developmental brain processes.

Awards and honors