Foxa1 and Foxa2 function both upstream of and cooperatively with Lmx1a and Lmx1b in a feedforward loop promoting mesodiencephalic dopaminergic neuron development

Abstract

Mesodiencephalic dopaminergic neurons control voluntary movement and reward based behaviours. Their dysfunction can lead to neurological disorders, including Parkinson's disease. These neurons are thought to arise from progenitors in the floor plate of the caudal diencephalon and midbrain. Members of the Foxa family of forkhead/winged helix transcription factor, Foxa1 and Foxa2, have previously been shown to regulate neuronal specification and differentiation of mesodiencephalic progenitors. However, Foxa1 and Foxa2 are also expressed earlier during regional specification of the rostral brain. In this paper, we have examined the early function of Foxa1 and Foxa2 using conditional mutant mice. Our studies show that Foxa1 and Foxa2 positively regulate Lmx1a and Lmx1b expression and inhibit Nkx2.2 expression in mesodiencephalic dopaminergic progenitors. Subsequently, Foxa1 and Foxa2 function cooperatively with Lmx1a and Lmx1b to regulate differentiation of mesodiencephalic dopaminergic neurons. Chromatin immunoprecipitation experiments indicate that Nkx2.2 and TH genes are likely direct targets of Foxa1 and Foxa2 in mesodiencephalic dopaminergic cells in vivo. Foxa1 and Foxa2 also inhibit GABAergic neuron differentiation by repressing the Helt gene in the ventral midbrain. Our data therefore provide new insights into the specification and differentiation of mesodiencephalic dopaminergic neurons and identifies Foxa1 and Foxa2 as essential regulators in these processes.

Doublesex and mab-3–related transcription factor 5 promotes midbrain dopaminergic identity in pluripotent stem cells by enforcing a ventral-medial progenitor fate

“…1A). Like Foxa2 and Lmx1a, Dmrt5 + cells occupy almost the entire thickness of the neural epithelium at E10.5 (6,12). The lateral boundaries of Dmrt5 expression lie immediately ventral to Nkx2.2 + neuroepithelium (Fig.…”

“…The embryos were allowed to develop for 24 h until st.17 and were analyzed for expression of Foxa2, a medial midbrain marker, and Mab21l2, a gene shown to maintain dorsal identities in early neural development (8). Both genes are highly conserved between the mouse and chick and show a nonoverlapping, spatially restricted expression pattern in the developing midbrain (8,12).…”

“…For example, the Lmx1a + Foxa2 + FP exclusively gives rise to mDA neurons, whereas the ventral-lateral domains marked by Meis2, Mab21l2, Helt, and Lhx1 produce glutamatergic or GABAergic neurons (6)(7)(8)(9). Perturbation of such a transcription "code" seen in genetic studies often led to misspecification of progenitor identity and subsequently to neural transmitter phenotypes (10)(11)(12). These studies demonstrate the mechanism of cell-fate determination to be a balance of the activation of "specification" programs and the repression of alternative fates, as observed in the spinal cord (13).…”

Human midbrain precursors activate the expected developmental genetic program and differentiate long-term to functional A9 dopamine neurons in vitro. Enhancement by Bcl-XL

“…Nurrl expression in the mouse (cooperating with Pitx3) is critical for the acquisition of the correct DA phenotype (that requires co-expression of TH, AADC, VMAT2 and DAT) [17,22,73,74]. In relation to LMX1B, loss of function studies indicate that is required for the maintenance of VM DAn [75], and more recently it has been involved in patterning [12,18,76]. hVMl cells activate NURR1 and LMX1B during the first week of differentiation (Fig.…”

Induced Pluripotent Stem Cell Technology and Direct Conversion: New Possibilities to Study and Treat Parkinson’s Disease

“…The combination of the three neurodevelopmental factors (BAM) with factors known to be crucially involved in the embryonic development of mDA neurons as well as for their beneficial effect for DA differentiation of ESCs [63][64][65][66][67][68] seem to specifically boost the transdifferentiation towards DA-like neurons. Even though these findings provide a proof of principle for the amazing possibility to directly transdifferentiate/convert somatic cells just by simple forced expression of a specific set of transcription factors, also for iDA neurons a very thorough characterization would be necessary before one could seriously consider their clinical application.…”