The when and where of floor plate induction.
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Animals↗
Biomedical subjects
T M Jessell
Publications and source records attributed to T M Jessell.
Neuronal patterning by BMPs: a requirement for GDF7 in the generation of a discrete class of commissural interneurons in the mouse spinal cord.
Inductive factors are known to direct the regional differentiation of the vertebrate central nervous system (CNS) but their role in the specification of individual neuronal cell types is less clear. We have examined the function of GDF7, a BMP family member expressed selectively by roof plate cells, in the generation of neuronal cell types in the dorsal spinal cord. We find that GDF7 can promote the differentiation in vitro of two dorsal sensory interneuron classes, D1A and D1B neurons. In Gdf7-null mutant embryos, the generation of D1A neurons is eliminated but D1B neurons and other identified dorsal interneurons are unaffected. These findings show that GDF7 is an inductive signal from the roof plate required for the specification of neuronal identity in the dorsal spinal cord and that GDF7 and other BMP family members expressed by the roof plate have non-redundant functions in vivo. More generally, these results suggest that BMP signaling may have a prominent role in the assignment of neuronal identity within the mammalian CNS.
Amino Acid Sequence↗
Functionally related motor neuron pool and muscle sensory afferent subtypes defined by coordinate ETS gene expression.
Motor function depends on the formation of selective connections between sensory and motor neurons and their muscle targets. The molecular basis of the specificity inherent in this sensory-motor circuit remains unclear. We show that motor neuron pools and subsets of muscle sensory afferents can be defined by the expression of ETS genes, notably PEA3 and ER81. There is a matching in PEA3 and ER81 expression by functionally interconnected sensory and motor neurons. ETS gene expression by motor and sensory neurons fails to occur after limb ablation, suggesting that their expression is coordinated by signals from the periphery. ETS genes may therefore participate in the development of selective sensory-motor circuits in the spinal cord.
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Specification of motor neuron identity by the MNR2 homeodomain protein.
Sonic hedgehog signaling controls the differentiation of motor neurons in the ventral neural tube, but the intervening steps are poorly understood. A differential screen of a cDNA library derived from a single Shh-induced motor neuron has identified a novel homeobox gene, MNR2, expressed by motor neuron progenitors and transiently by postmitotic motor neurons. The ectopic expression of MNR2 in neural cells initiates a program of somatic motor neuron differentiation characterized by the expression of homeodomain proteins, by neurotransmitter phenotype, and by axonal trajectory. Our results suggest that the Shh-mediated induction of a single transcription factor, MNR2, is sufficient to direct somatic motor neuron differentiation.
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Motor neuron-derived retinoid signaling specifies the subtype identity of spinal motor neurons.
The diversification of neuronal cell types in the vertebrate central nervous system depends on inductive signals provided by local organizing cell groups of both neural and nonneural origin. The influence of signals provided by postmitotic neurons on the fate of neurons born at subsequent development stages, however, remains unclear. We provide evidence that a retinoid-mediated signal provided by one subset of early-born spinal motor neurons imposes a local variation in the number of motor neurons generated at different axial levels and also specifies the identity of a later-born subset of motor neurons. Thus, in the vertebrate central nervous system the distinct fates of late-born neurons may be acquired in response to signals provided by early-born neurons.
Aldehyde Oxidoreductases↗
A role for rhoB in the delamination of neural crest cells from the dorsal neural tube.
The differentiation of neural crest cells from progenitors located in the dorsal neural tube appears to involve three sequential steps: the specification of premigratory neural crest cell fate, the delamination of these cells from the neural epithelium and the migration of neural crest cells in the periphery. BMP signaling has been implicated in the specification of neural crest cell fate but the mechanisms that control the emergence of neural crest cells from the neural tube remain poorly understood. To identify molecules that might function at early steps of neural crest differentiation, we performed a PCR-based screen for genes induced by BMPs in chick neural plate cells. We describe the cloning and characterization of one gene obtained from this screen, rhoB, a member of the rho family GTP-binding proteins. rhoB is expressed in the dorsal neural tube and its expression persists transiently in migrating neural crest cells. BMPs induce the neural expression of rhoB but not the more widely expressed rho family member, rhoA. Inhibition of rho activity by C3 exotoxin prevents the delamination of neural crest cells from neural tube explants but has little effect on the initial specification of premigratory neural crest cell fate or on the later migration of neural crest cells. These results suggest that rhoB has a role in the delamination of neural crest cells from the dorsal neural tube.
Amino Acid Sequence↗
Chordin regulates primitive streak development and the stability of induced neural cells, but is not sufficient for neural induction in the chick embryo.
We have investigated the role of Bone Morphogenetic Protein 4 (BMP-4) and a BMP antagonist, chordin, in primitive streak formation and neural induction in amniote embryos. We show that both BMP-4 and chordin are expressed before primitive streak formation, and that BMP-4 expression is downregulated as the streak starts to form. When BMP-4 is misexpressed in the posterior area pellucida, primitive streak formation is inhibited. Misexpression of BMP-4 also arrests further development of Hensen's node and axial structures. In contrast, misexpression of chordin in the anterior area pellucida generates an ectopic primitive streak that expresses mesoderm and organizer markers. We also provide evidence that chordin is not sufficient to induce neural tissue in the chick. Misexpression of chordin in regions outside the future neural plate does not induce the early neural markers L5, Sox-3 or Sox-2. Furthermore, neither BMP-4 nor BMP-7 interfere with neural induction when misexpressed in the presumptive neural plate before or after primitive streak formation. However, chordin can stabilise the expression of early neural markers in cells that have already received neural inducing signals. These results suggest that the regulation of BMP signalling by chordin plays a role in primitive streak formation and that chordin is not sufficient to induce neural tissue.
Amino Acid Sequence↗
Integrated FGF and BMP signaling controls the progression of progenitor cell differentiation and the emergence of pattern in the embryonic anterior pituitary.
The mechanisms by which inductive signals control the identity, proliferation and timing of differentiation of progenitor cells in establishing spatial pattern in developing vertebrate tissues remain poorly understood. We have addressed this issue in the embryonic anterior pituitary, an organ in which distinct hormone cell types are generated in a precise temporal and spatial order from an apparently homogenous ectodermal primordium. We provide evidence that in this tissue the coordinate control of progenitor cell identity, proliferation and differentiation is imposed by spatial and temporal restrictions in FGF- and BMP-mediated signals. These signals derive from adjacent neural and mesenchymal signaling centers: the infundibulum and ventral juxtapituitary mesenchyme. The infundibulum appears to have a dual signaling function, serving initially as a source of BMP4 and subsequently of FGF8. The ventral juxtapituitary mesenchyme appears to serve as a later source of BMP2 and BMP7. In vitro, FGFs promote the proliferation of progenitor cells, prevent their exit from the cell cycle and contribute to the specification of progenitor cell identity. BMPs, in contrast, have no apparent effect on cell proliferation but instead appear to act with FGFs to control the initial selection of thyrotroph and corticotroph progenitor identity.
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The control of rostrocaudal pattern in the developing spinal cord: specification of motor neuron subtype identity is initiated by signals from paraxial mesoderm.
The generation of distinct classes of motor neurons is an early step in the control of vertebrate motor behavior. To study the interactions that control the generation of motor neuron subclasses in the developing avian spinal cord we performed in vivo grafting studies in which either the neural tube or flanking mesoderm were displaced between thoracic and brachial levels. The positional identity of neural tube cells and motor neuron subtype identity was assessed by Hox and LIM homeodomain protein expression. Our results show that the rostrocaudal identity of neural cells is plastic at the time of neural tube closure and is sensitive to positionally restricted signals from the paraxial mesoderm. Such paraxial mesodermal signals appear to control the rostrocaudal identity of neural tube cells and the columnar subtype identity of motor neurons. These results suggest that the generation of motor neuron subtypes in the developing spinal cord involves the integration of distinct rostrocaudal and dorsoventral patterning signals that derive, respectively, from paraxial and axial mesodermal cell groups.
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A role for the roof plate and its resident TGFbeta-related proteins in neuronal patterning in the dorsal spinal cord.
Distinct neuronal cell types are generated at characteristic times and positions in the dorsal horn of the spinal cord. We provide evidence that the identity and pattern of generation of dorsal neurons depend initially on BMP-mediated signals that derive from the epidermal ectoderm and induce dorsal midline cells of the roof plate. Roof plate cells provide a secondary source of TGFbeta-related signals that are required for the generation of distinct classes of dorsal interneurons. These inductive interactions involve both qualitative and quantitative differences in signaling by TGFbeta-related factors and temporal changes in the response of neural progenitor cells.
Activins↗
Pax6 controls progenitor cell identity and neuronal fate in response to graded Shh signaling.
Distinct classes of motor neurons and ventral interneurons are generated by the graded signaling activity of Sonic hedgehog (Shh). Shh controls neuronal fate by establishing different progenitor cell populations in the ventral neural tube that are defined by the expression of Pax6 and Nkx2.2. Pax6 establishes distinct ventral progenitor cell populations and controls the identity of motor neurons and ventral interneurons, mediating graded Shh signaling in the ventral spinal cord and hindbrain.
Animals↗
Independent requirement for ISL1 in formation of pancreatic mesenchyme and islet cells.
The mammalian pancreas is a specialized derivative of the primitive gut endoderm and controls many homeostatic functions through the activity of its component exocrine acinar and endocrine islet cells. The LIM homeodomain protein ISL1 is expressed in all classes of islet cells in the adult and its expression in the embryo is initiated soon after the islet cells have left the cell cycle. ISL1 is also expressed in mesenchymal cells that surround the dorsal but not ventral evagination of the gut endoderm, which together comprise the pancreatic anlagen. To define the role of ISL1 in the development of the pancreas, we have now analysed acinar and islet cell differentiation in mice deficient in ISL1 function. Dorsal pancreatic mesenchyme does not form in ISL1-mutant embryos and there is an associated failure of exocrine cell differentiation in the dorsal but not the ventral pancreas. There is also a complete loss of differentiated islet cells. Exocrine, but not endocrine, cell differentiation in the dorsal pancreas can be rescued in vitro by provision of mesenchyme derived from wild-type embryos. These results indicate that ISL1, by virtue of its requirement for the formation of dorsal mesenchyme, is necessary for the development of the dorsal exocrine pancreas, and also that ISL1 function in pancreatic endodermal cells is required for the generation of all endocrine islet cells.
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Assignment of early caudal identity to neural plate cells by a signal from caudal paraxial mesoderm.
The early patterning of the vertebrate central nervous system involves the generation of progenitor cells with distinct fates at rostral and caudal levels of the neuraxis. We provide evidence that the assignment of early rostrocaudal differences in progenitor cell properties is established by spatial restrictions in the signaling properties of the paraxial mesoderm and epidermal ectoderm. Caudal level paraxial mesoderm secretes a factor, distinct from retinoic acid or fibroblast growth factors (FGFs), that can impose caudal fates on prospective anterior proencephalic progenitors. The caudalizing activity of the paraxial mesoderm can, however, be induced by FGF signaling. The distinct properties of cells at rostral and caudal levels of the neural plate appear to depend, in addition, on the early exclusion of bone morphogenetic proteins (BMPs) from rostral level epidermal ectoderm. Thus, differences in the signaling properties of cell groups that flank the neural plate appear to contribute to the early rostrocaudal identity of neural cells, distinguishing progenitor cells at prospective anterior proencephalic regions from those at more caudal levels of the neuraxis.
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Graded sonic hedgehog signaling and the specification of cell fate in the ventral neural tube.
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Animals↗
Two critical periods of Sonic Hedgehog signaling required for the specification of motor neuron identity.
Antibodies that block Sonic Hedgehog (SHH) signaling have been used to show that SHH activity is required for the induction of floor plate differentiation by the notochord and independently for the induction of motor neurons by both the notochord and midline neural cells. Motor neuron generation depends on two critical periods of SHH signaling: an early period during which naive neural plate cells are converted into ventralized progenitors and a late period that extends well into S phase of the final progenitor cell division, during which SHH drives the differentiation of ventralized progenitors into motor neurons. The ambient SHH concentration during the late period determines whether ventralized progenitors differentiate into motor neurons or interneurons, thus defining the pattern of neuronal cell types generated in the neural tube.
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Diversity and pattern in the developing spinal cord.
The generation of distinct neuronal cell types in appropriate numbers and at precise positions underlies the assembly of neural circuits that encode animal behavior. Despite the complexity of the vertebrate central nervous system, advances have been made in defining the principles that control the diversification and patterning of its component cells. A combination of molecular genetic, biochemical, and embryological assays has begun to reveal the identity and mechanism of action of molecules that induce and pattern neural tissue and the role of transcription factors in establishing generic and specific neuronal fates. Some of these advances are discussed here, focusing on the spinal cord as a model system for analyzing the molecular control of central nervous system development in vertebrates.
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Requirement for LIM homeobox gene Isl1 in motor neuron generation reveals a motor neuron-dependent step in interneuron differentiation.
Motor neuron differentiation is accompanied by the expression of a LIM homeodomain transcription factor, Islet1 (ISL1). To assess the involvement of ISL1 in the generation of motor neurons, we analyzed cell differentiation in the neural tube of embryos in which ISL1 expression has been eliminated by gene targeting. Motor neurons are not generated without ISL1, although many other aspects of cell differentiation in the neural tube occur normally. A population of interneurons that express Engrailed1 (EN1), however, also fails to differentiate in Isl1 mutant embryos. The differentiation of EN1+ interneurons can be induced in both wild-type and mutant neural tissue by regions of the neural tube that contain motor neurons. These results show that ISL1 is required for the generation of motor neurons and suggest that motor neuron generation is required for the subsequent differentiation of certain interneurons.
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Development: neural development: are there any surprises left?
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Animals↗