The people behind the papers – Laura Lahti and Thomas Perlmann

Laura Lahti (left) and Thomas Perlmann (right). Photo credit: Behzad Yaghmaeian Salmani.

Thomas, what questions are your lab trying to answer?

TP: We aim to understand how midbrain dopamine neurons develop and function. These neurons come in different flavours, with each subtype playing distinct roles. Some are particularly sensitive and selectively degenerate in Parkinson's disease, leading to the hallmark motor symptoms of the disorder. We are particularly fascinated by the origins and characteristics of this neuronal diversity – how it arises and what it looks like at a molecular level. To explore this, we use single-cell RNA sequencing and other advanced techniques to dissect the molecular diversity of these neurons and uncover the factors that define their differential vulnerability.

Laura, how did you come to work in the lab and what drives your research today?

LL: For my Master's thesis and PhD thesis at the University of Helsinki, I studied the early development of the midbrain and hindbrain region, including the dopamine neurons. I had followed the Perlmann group's research for years, and when I saw that they were looking for a postdoc, I applied. Much to my surprise, I got the job. I still find this topic fascinating and want to understand how the diversity of dopamine neurons is generated during development – for example, are there some determinants functioning already at the progenitor level, or is the process regulated by some signals from the microenvironment during the dopamine differentiation, or is it perhaps a combination of both?

Can you tell us about the background of the field that inspired your work?

TP: Developmental neuroscience is a fundamental and dynamic field that seeks to unravel how the most complex structure in the universe ­­– the human brain – is formed. One fascinating aspect is the generation of dopamine neurons, which has long been a subject of intense research. Our lab has contributed significantly to this field by identifying key transcriptional mechanisms that regulate the early development and maturation of dopamine neurons.

Dopamine neurons serve as an excellent model for understanding how neurons are specified and differentiated. Beyond their fundamental biological significance, these neurons are of great clinical importance. The potential to use stem cell-derived dopamine neuron precursors for transplantation in Parkinson's disease has further amplified interest in their early development. Insights into the mechanisms governing dopamine neuron formation are crucial for refining protocols to generate high-quality, clinically viable cells for transplantation, bringing us closer to developing effective cell-based therapies.

Can you give us the key results of the paper in a paragraph?

LL: We wanted to understand the balance of proliferation and neurogenesis in the dopamine progenitor domain, and we were able to identify a set of transcription factors that appeared to regulate this balance: Sox9, nuclear factor I/B (Nfib) and nuclear factor I/X (Nfix). When we inactivated these genes in the early midbrain, we could see that the progenitors remained in the cell cycle a bit longer and generated more neurons, which in turn delayed the maturation of ependymal cells. We also investigated what happens to dopamine progenitors after they have given rise to all the dopamine neurons. They don't seem to generate any glia, but exit the cell cycle and become very specific type of ependymal cells, which, to some extent, resemble the cells found in circumventricular organs in other parts of the brain.

When doing the research, did you have any particular result or eureka moment that has stuck with you?

LL: First, I attempted to inactivate our candidate genes with Lmx1a-CreERT2, but it was too weak to recombine the floxed alleles. When I switched to En1-Cre, which inactivated all alleles very effectively, I could immediately observe a clear phenotype in progenitors and neurons, and that was a great relief.

And what about the flipside: any moments of frustration or despair?

LL: After having studied the development of midbrain for over two decades now, frustration and despair are two words that characterise the whole experience pretty accurately. In this project in particular, collecting the double and triple conditional mutants for all the necessary quantifications was the worst bottleneck. It took years. We also had two incidences of mouse parvovirus at our animal facility, which at one point prevented access to mice for over 6 months, and then we had to re-derive all the lines when we moved the mice to new facility, which also took a while. I often berated myself that I had not chosen to study some fun little worms instead. I also tried countless things – from transplantations to AAV injections – to activate the adult midbrain ependymal cells in vivo but nothing worked. I probably have a terabyte of carefully documented negative results on a hard drive.

Why did you choose to submit this paper to Development?

TP: Development is known for publishing high-quality, well-executed studies that advance our understanding of developmental mechanisms. Its rigorous standards and strong reputation make it a highly respected journal within the developmental biology community. Given the relevance of our work to the field, we saw Development as an excellent platform to share our findings with researchers who are equally committed to exploring the fundamental processes that shape development of the brain's dopaminergic system.

LL: Development is my favourite journal, and I had good experiences with publishing there before. I didn't even consider sending this work anywhere else. I first thought about going through the Review Commons, but then realised that we'd send it to Development anyway after that (if we got any positive reviews that is) so we submitted directly instead.

Laura, what is next for you after this paper?

LL: I have been employed in this group as a staff scientist for several years now and would like to stay here and continue with other projects, for as long as it is possible. At least so far, they seem to be going more smoothly than this project.

Thomas, where will this story take your lab next?

TP: Laura's research has provided key insights into how quiescence is established during embryogenesis, revealing the mechanisms that regulate the precise timing and location of dopamine neuron generation. Building on these findings, we now aim to investigate how early developmental regulatory mechanisms contribute to the specification of distinct dopamine neuron subtypes, an important question that remains largely unanswered. Our focus will be on the dopamine neuron subtypes that are most vulnerable in Parkinson's disease, with the goal of advancing our understanding of their development and potential therapeutic applications.