Marten Smidt

Within that team the Smidtlab focuses on fundamental processes of brain development and has especially expertise on the molecular programming on midbrain dopaminergic neurons and their role in Parkinson's Disease. 

The expertise has lead to the development of a master program on Molecular Neurosciences here at the UVA, being part of the Neurobiology cluster of Biomedical sciences master programmes

Current research lines within the molecular programming of dopaminergic neurons:

1. Investigate the role of epigentic mechanisms on molecular specification of mdDA neurons
2. Understand the role of critical transcription factors in cortical development
3. Investigate mechanisms of dopamine modulation.

4. Investigate mechanisms of specific cell death as found in SNc neurons.

Research background

My main interest is molecular programming during development of the central nervous system. Since at that time almost nothing was known on the subject, I started with JPH Burbach a cloning effort to identify transcription factors that play a role during CNS development. From this work three major breakthroughs were established:
1. The cloning, identification and characterization of the homeobox gene Pitx3 [Smidt MP pnas 1997]. This gene was found to beexclusively expressed in the substantia nigra (SNc) and ventral tegmental area (VTA) forming the midbrain dopamine system, essential for mood and movement regulation in mammals. The real impact of the work was that this factor is exclusively expressed in these neurons and this formed the first step in the understanding of molecular programming of midbrain dopamine neurons.
2. The identification of the role of the orphan nuclear hormone receptor Nurr1  [Saucedo-Cardenas pnas 1998]. It was shown by us and others that Nurr1 is essential for the development of fully differentiated midbrain dopamine neurons. This was the second factor identified to be involved in midbrain dopamine neurodevelopment.
3. The identification of Lmx1b (publication [Smidt MP nat-neurosc.-2000]. We showed that the early specification of the midbrain by Lmx1b is essential for the formation of midbrain dopaminergic neurons. Moreover, we showed that TH expression was possible in early DA neurons without the expression of Pitx3, indicating that Pitx3 might be involved in molecular processes other than transmitter phenotype. 
After this cloning and descriptive phase I was interested to go into depth into the role of Pitx3 (as an NWO fellow) in the neurodevelopment of midbrain dopamine neurons and to broaden my view on molecular signaling events in neuronal cells. This was accomplished by the start of analysis of the Pitx3 knock out and by the start of a new research line on forkhead proteins (FoxO and FoxK family). The work lead to three major findings:
1. The data from the Pitx3 knock-out analysis (aphakia mouse) formed anew chapter in the understanding of the role of Pitx3 in the development of midbrain dopamine neurons (publication [enu:Smidt-MP development-2004]). We showed that Pitx3 is essential for the formation of the SNc and the ventral part of the VTA. Moreover it was clear from the analysis that the defect was apparent at the early stage of terminal differentiation, Most importantly, the defect was not present in all midbrain dopamine neurons but mainly in the ventral medial SNc and ventral VTA.
2. The cloning and functional characterization of FoxO6, a novel member of the FoxO family (FoxO1, FoxO3 and FoxO4). We showed that FoxO6 had unique properties in terms of nucleo-cytoplasmic shuttling, as a result of PKB signaling, compared to its family members  [Jacobs FM jbc2003]. Later we showed the mechanism of the altered shuttling behavior and showed that phosphorylation by PKB does inactivate FoxO6 by inhibiting DNA interaction without the extra level of inhibition of nuclear removal (publication [enu:van-der-Heide BJ 2005]). We have gained quickly a good position by this work. A review from our team received much enthusiasm as highlighted by 82 citations so-far and the 25th place of most downloaded papers in the publication year [Van-Der-Heide BJ review 2004].
3. The identification a novel factor of the FoxK family, namely (mouse) Foxk2. This factor was, based on sequence homology, the designated orthologue of yeast Fkh2 which is essential in the progression of the cell-cycle (G2/M phase progression). Our analysis showed that the functional similarity is not apparent, Foxk2 has a function in cell-survival but does not stimulate the G2/M phase transition.
The fact that a subset of the complete group of dopamine neurons was affected in the Pitx3 knock-out (Pitx3 itself is expressed in all midbrain dopamine cells) initiated the novel idea that the molecular coding of the SNc and VTA is not the same. A real step forward was madeby the identification of subset specific markers and coding differences in the ventricular zone. This concept of subset specification was a crucial step in the way the field regarded the molecular pathways leading to the development of dopamine neurons of the SNc and VTA [Smits SM prog neurobiol-2006]. In addition, it became clear that the neurons populating the SNc and VTA are not generated exclusively in the midbrain but also in the diencephalon. Therefore, the name of this neuronal group was changed to mesodiencephalic dopaminergic (mdDA) neurons and has been used as such from that point on.
This was a crucial moment in my career, i established my own group and my work clearly surpassed the initial identification and function-description of transcription factors involved in the development of mdDA neurons. My interest went into two additionally research directions:
1. The live visualization of dopamine neurotransmission through multi-pinhole SPECT. Prof dr. Freek Beekman designed a spectacular micro-SPECT system to follow tracers in the mouse brain with a resolution of 0.3 mm. Together we started to image live dopamine transmitter events in a living mouse. This work has lead to two high impact publications [Beekman FJ nucl medicin 2005] and [Vastenhouw B mol psych 2007]. 
2. Understand how subset specification is established, which subsets exist and what the relationship is between subset and specific connectivity. A crucial finding in the understanding of subsets specific molecular coding was established through the identification of a subset specific transcriptional target of Pitx3. This gene, (retinal) aldehyde dehydrogenase 2 (Ahd2, Raldh1) is expressed, in the adult brain, in the ventral cells of the SNc and VTA, the neurons that are lost in the Pitx3 mutant  [Jacobs FM development 2007]. A second novel finding was that retinoic acid (RA) has a role in terminal differentiation of this specific set of neurons in addition to its role in the ventricularzone. Ahd2 is present in ventricular zone cells, its transcription is terminated when cells leave the ventricular zone and under the control of Pitx3, Ahd2 is transcribed again in a (lateral) subset of mdDA neurons and is essential for the synthesis of RA out of retinal. We were able to show the dependence of mdDA differentiation for RA signalling by rescuing the Pitx3 knock-out phenotype through the exogenous application of RA. 
Although I am still working on- and interested in the FoxO6 knock out (we have generated chimeric animals) my main interest lies with the molecular programming of mdDA neuronal subsets. My lab is currently investigating 1) why Ahd2 activation is only happening in the described subset; 2) we are mapping transcriptional targets of Engrailed, Lmx1a/b, and Nurr1 to get a better idea about the molecular programming that is initiated within mdDA neurons; 3) the functional interaction between Pitx3/Nurr1 and En1 and 4) we are finalizing the identification of adult subset specific markers. At this moment my research group consist of 3 PhD students, 2 technicians and every year about 3 master students.
The work described above has been very fruit-full and has lead to a leading position of my research group mainly in the field of development and engineering of mdDA neurons, marked by many invitations to write reviews/books on the topic, the high amount of peer-reviewed publications and the invitations to speak at the international level about my work. I have initiated a European collaboration called mdDANeurodev (see www.mdDAneurodev.eu) which was funded in the KP7 scheme (2008) and in addition i was awarded a VICI grant from NWO-ALW (2008/2009) to continue the fundamental work on the development of subsets of dopamine neurons.

IN 2017 I founded with Dr. Lars vd Heide a biotech company: Macrobian Biotech BV. Mission : 

Fundamental research in the neuroscience field with new technologies in genetics and transcriptomics together with far reaching gene function research has led to the discovery of mechanistic details that is unprecedented. The founders of Macrobian-Biotech are at the heart of such endeavors and that has lead to the identification of specific molecular pathways that regulate dopamine production specifically in midbrain dopamine neurons. Dysfunction of these neurons are at the center of neuro-psychiatric and neurological disorders such as Schizophrenia and Parkinson‘s. It is the ambition of Macrobian-Biotech to be at the forefront of clinical trial ready compound development vivifying novel treatments of neurological and neuropsychiatric diseases. 

please see Macrobianbiotech.com for more details.