Transcriptional repression coordinates the temporal switch from motor to serotonergic neurogenesis

Jacob, John R.; Ferri, Luca; Milton, Christopher; Prin, Fabrice; Pla, Patrick; Lin, Wei; Gavalas, Anthony; Ang, Siew Lan; Briscoe, James

doi:10.1038/nn1985

Cited by 79 publications

(111 citation statements)

References 50 publications

Supporting

Mentioning

107

Contrasting

Order By: Relevance

“…In contrast, the Isl1/2ϩ 3N cohort is relatively unlabeled in our fate maps. We posit a model in which a common progenitor pool first generates Isl1/2ϩ motorneurons and subsequently generates the Brn3a cohort, akin to the sequential generation of motor and serotonin neurons observed in the hindbrain (36,37). In our study, Isl1/2ϩ 3N neurons appear to arise from progenitors immediately adjacent to the Shh domain (at 9.5 dpc).…”

Section: Discussionmentioning

confidence: 84%

Spatiotemporally separable Shh domains in the midbrain define distinct dopaminergic progenitor pools

Joksimovic

Anderegg

Roy

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

106

121

View full text Add to dashboard Cite

Midbrain dopamine neurons (mDA) are important regulators of diverse physiological functions, including movement, attention, and reward behaviors. Accordingly, aberrant function of dopamine neurons underlies a wide spectrum of disorders, such as Parkinson's disease (PD), dystonia, and schizophrenia. The distinct functions of the dopamine system are carried out by neuroanatomically discrete subgroups of dopamine neurons, which differ in gene expression, axonal projections, and susceptibility in PD. The developmental underpinnings of this heterogeneity are undefined. We have recently shown that in the embryonic CNS, mDA originate from the midbrain floor plate, a ventral midline structure that is operationally defined by the expression of the molecule Shh. Here, we develop these findings to reveal that in the embryonic midbrain, the spatiotemporally dynamic Shh domain defines multiple progenitor pools. We deduce 3 distinct progenitor pools, medial, intermediate, and lateral, which contribute to different mDA clusters. The earliest progenitors to express Shh, here referred to as the medial pool, contributes neurons to the rostral linear nucleus and mDA of the ventral tegmental area/interfascicular regions, but remarkably, little to the substantia nigra pars compacta. The intermediate Shh؉ progenitors give rise to neurons of all dopaminergic nuclei, including the SNpc. The last and lateral pool of Shh؉ progenitors generates a cohort that populates the red nucleus, Edinger Westphal nucleus, and supraoculomotor nucleus and cap. Subsequently, these lateral Shh؉ progenitors produce mDA. This refined ontogenetic definition will expand understanding of dopamine neuron biology and selective susceptibility, and will impact stem cell-derived therapies and models for PD.dopamine ͉ Sonic hedgehog ͉ lineage ͉ substantia nigra

show abstract

Section: Discussionmentioning

confidence: 84%

Spatiotemporally separable Shh domains in the midbrain define distinct dopaminergic progenitor pools

Joksimovic

Anderegg

Roy

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

106

121

View full text Add to dashboard Cite

show abstract

“…Thus, the maintenance of the Nkx2.2 expression domains by Otx2 is via a pathway independent of that of the Foxa2 restriction on the Nkx2.2 expression domain in the ventral midbrain. Given that Foxa2 coexpresses with Nkx2.2 in a population of hindbrain cells (28), it is conceivable that Foxa2 regulates Nkx2.2 cooperatively with a region-specific partner.…”

Section: Discussionmentioning

confidence: 99%

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

Gennet

Gale

Nan

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Understanding the control of cell-fate choices during embryonic stem cell (ESC) differentiation is crucial for harnessing strategies for efficient production of desired cell types for pharmaceutical drug screening and cell transplantation. Here we report the identification of the zinc finger-like doublesex and mab-3-related transcription factor 5 (Dmrt5) as a marker for mammalian ventralmedial mesencephalic neuroepithelium that give rise to dopamine neurons. Gain-and loss-of-function studies in ESC demonstrate that Dmrt5 is critically involved in the specification of ventralmedial neural progenitor cell fate and the subsequent generation of dopamine neurons expressing essential midbrain characteristics. Genome-wide analysis of Dmrt5-mediated transcriptome changes and expression profiling of ventral-medial and ventral-lateral mesencephalic neuroepithelium revealed suppressive and inductive regulatory roles for Dmrt5 in the transcription program associated with the ventral-medial neural progenitor fates. Together, these data identify Dmrt5 as an important player in ventral mesencephalic neural fate specification.A major goal of embryonic stem cell (ESC) research is to direct the cells' differentiation toward specific cell types, especially those targeted by devastating degenerative diseases. The advent of induced pluripotent stem cell technology, with its promise for disease modeling, drug screening, and cell therapy, places further demand on a better understanding on the control of lineage/cell-fate specification from pluripotent stem cells. One neuronal cell type in particular, the midbrain dopaminergic (mDA) neuron, is a prime target in applied stem cell research because of its association with Parkinson's disease.The mDA neurons are generated in the floor plate (FP) region of the ventral midbrain and are uniquely identified by their coexpression of tyrosine hydroxylase (TH) with the mDA-specific homeobox protein Pitx3 (1, 2). During development, local inductive signals-Shh, FGF8, and Wnt1-induce distinct cell-fate potentials through initiation of transcriptional cascades that govern the subsequent differentiation, migration, and maturation of the ventral-most progenitors into mDA neurons (3-5). The distinct cell-fate potentials of ventral midbrain progenitors are defined by domain-identifiable expression of transcription factors. 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 (6-9). Perturbation of such a transcription "code" seen in genetic studies often led to misspecification of progenitor identity and subsequently to neural transmitter phenotypes (10-12). 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). However, how transcription factors coordinate distinct fate choice in the ventral midbrain remains poorl...

show abstract

“…A first set of transcription factors, Nkx2.2, Nkx2.9, and Ascl1, are required to generate 5-HT precursors in the raphe between embryonic days 8 and 10, in mice. A second set of transcription factors, GATA2, GATA3, Insm1, Fox A2, Lmx1b, and Pet1, are required for 5-HT subtype selection and 5-HT neuron terminal differentiation between E10 and E12 (Cordes, 2005;Jacob et al, 2007;Jacob et al, 2009). Other transcription factors, such as Phox2B and Hoxb1, are involved in repressing the 5-HT phenotype of the precursors in specific brainstem regions (Pattyn et al, 2004).…”

Section: Targeting the Development Of 5-ht Neurons In The Raphementioning

confidence: 99%

Genetic Models of Serotonin (5‐HT) Depletion: What do They Tell Us About the Developmental Role of 5‐HT?

Trowbridge¹,

Narboux-Nême²,

Gaspar³

2010

The Anatomical Record

View full text Add to dashboard Cite

A large number of hyposerotonergic genetic models have been generated over the past few years. Serotonin (5-HT) depletion has been obtained via targeting of genes involved in 5-HT synthesis (Tph1 and Tph2), specification and determination of the 5-HT phenotype during development (GATA3, Pet1, and Lmx1b), and 5-HT storage or clearance (Vmat2 and SERT). Here we review these various models from a developmental perspective, beginning with a description of the sources of 5-HT during development. We then summarize the neurological and behavioral alterations that have been observed in the genetic hyposerotonergic models. Although these models appear to have normal brain development and do not exhibit any gross morphological defects, problems in somatic growth and physiological functions have been observed. Abnormal adult behavior is also seen, although whether it results from depletion of 5-HT during development or functional 5-HT deficiencies in adult life remains unclear. Evidence from these hyposerotonergic models suggests that the developing brain may not need 5-HT for the establishment of general organization and structure. However, central 5-HT appears to be necessary for postnatal body growth, maturation of respiratory and vegetative control, and possibly for the development of normal adult behavior. Anat Rec, 294:1615Rec, 294: -1623Rec, 294: , 2011. V V C 2011 Wiley-Liss, Inc.

show abstract

Transcriptional repression coordinates the temporal switch from motor to serotonergic neurogenesis

Cited by 79 publications

References 50 publications

Spatiotemporally separable Shh domains in the midbrain define distinct dopaminergic progenitor pools

Spatiotemporally separable Shh domains in the midbrain define distinct dopaminergic progenitor pools

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

Genetic Models of Serotonin (5‐HT) Depletion: What do They Tell Us About the Developmental Role of 5‐HT?

Contact Info

Product

Resources

About