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From induction to conduction: how intrinsic transcriptional priming of extrinsic neuronal connectivity shapes neuronal identity.

Russ JB, Kaltschmidt JA - Open Biol (2014)

Bottom Line: As the neuron's early connectivity is established, extrinsic signals from its pre- and postsynaptic partners feedback on the neuron to further refine its unique characteristics.As a result, disruption of one component of the circuitry during development can have vital consequences for the proper identity specification of its synaptic partners.Recent studies have begun to harness the power of various transcription factors that control neuronal cell fate, including those that specify a neuron's subtype-specific identity, seeking insight for future therapeutic strategies that aim to reconstitute damaged circuitry through neuronal reprogramming.

View Article: PubMed Central - PubMed

Affiliation: Weill Cornell/Rockefeller University/Sloan Kettering Tri-Institutional MD-PhD Program, New York, NY 10065, USA Neuroscience Program, Weill Cornell Medical College, New York, NY 10065, USA Developmental Biology Program, Sloan Kettering Institute, New York, NY 10065, USA.

ABSTRACT
Every behaviour of an organism relies on an intricate and vastly diverse network of neurons whose identity and connectivity must be specified with extreme precision during development. Intrinsically, specification of neuronal identity depends heavily on the expression of powerful transcription factors that direct numerous features of neuronal identity, including especially properties of neuronal connectivity, such as dendritic morphology, axonal targeting or synaptic specificity, ultimately priming the neuron for incorporation into emerging circuitry. As the neuron's early connectivity is established, extrinsic signals from its pre- and postsynaptic partners feedback on the neuron to further refine its unique characteristics. As a result, disruption of one component of the circuitry during development can have vital consequences for the proper identity specification of its synaptic partners. Recent studies have begun to harness the power of various transcription factors that control neuronal cell fate, including those that specify a neuron's subtype-specific identity, seeking insight for future therapeutic strategies that aim to reconstitute damaged circuitry through neuronal reprogramming.

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Related in: MedlinePlus

Fezf2 and Ptf1a are necessary and sufficient for a subtype-specific identity. Column 1 illustrates the role of Fezf2 in controlling CFuPN identity. In Fezf2−/− mice (row 1), CFuPNs primarily acquire a CPN identity, which causes these cells to project axons across the corpus callosum rather than to subcortical targets [10,32]. Misexpression of Fezf2 (+Fezf2) in CPNs or layer IV pyramidal cells in the cortex (rows 2 and 3), or in striatal medium spiny neurons (MSNs) (row 4), is sufficient to convert their identity to resemble that of CFuPNs, which includes changes in their molecular profile, neuronal morphology, and projection of axons to subcortical targets [11,12,33,34]. In the case of MSNs, this also includes a change in neurotransmitter status from inhibitory to excitatory [34]. Column 2 illustrates the role of Ptf1a in controlling an inhibitory neuronal identity in various regions of the CNS. Ptf1a is necessary for specifying the identity of dI4 interneurons in the spinal cord, inhibitory interneurons and Purkinje cells in the cerebellum, and amacrine and horizontal cells in the retina (rows 1–3). Without Ptf1a expression (Ptf1a−/−), these neurons adopt the features of their excitatory counterparts: dI5 cells in the spinal cord, granule cells in the cerebellum and retinal ganglion cells (RGCs) in the retina [13–17]. Misexpression of Ptf1a (+Ptf1a) in the developing spinal cord (row 4), cerebellum (row 5) or retina (row 6) is sufficient to promote an inhibitory interneuronal identity, causing dI5 cells to differentiate with dI4 properties in the spinal cord, granule cells to differentiate with inhibitory interneuron or Purkinje cell properties in the cerebellum, and RGCs to differentiate with amacrine and horizontal cell properties in the retina [35–40]. Misexpression of Ptf1a in cortical pyramidal cells (row 7) is sufficient to induce features of an inhibitory peptidergic identity, including an alteration in cellular morphology and neurotransmitter status [19]. ‘+’ indicates an excitatory neurotransmitter status, ‘−’ indicates an inhibitory neurotransmitter status.
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RSOB140144F1: Fezf2 and Ptf1a are necessary and sufficient for a subtype-specific identity. Column 1 illustrates the role of Fezf2 in controlling CFuPN identity. In Fezf2−/− mice (row 1), CFuPNs primarily acquire a CPN identity, which causes these cells to project axons across the corpus callosum rather than to subcortical targets [10,32]. Misexpression of Fezf2 (+Fezf2) in CPNs or layer IV pyramidal cells in the cortex (rows 2 and 3), or in striatal medium spiny neurons (MSNs) (row 4), is sufficient to convert their identity to resemble that of CFuPNs, which includes changes in their molecular profile, neuronal morphology, and projection of axons to subcortical targets [11,12,33,34]. In the case of MSNs, this also includes a change in neurotransmitter status from inhibitory to excitatory [34]. Column 2 illustrates the role of Ptf1a in controlling an inhibitory neuronal identity in various regions of the CNS. Ptf1a is necessary for specifying the identity of dI4 interneurons in the spinal cord, inhibitory interneurons and Purkinje cells in the cerebellum, and amacrine and horizontal cells in the retina (rows 1–3). Without Ptf1a expression (Ptf1a−/−), these neurons adopt the features of their excitatory counterparts: dI5 cells in the spinal cord, granule cells in the cerebellum and retinal ganglion cells (RGCs) in the retina [13–17]. Misexpression of Ptf1a (+Ptf1a) in the developing spinal cord (row 4), cerebellum (row 5) or retina (row 6) is sufficient to promote an inhibitory interneuronal identity, causing dI5 cells to differentiate with dI4 properties in the spinal cord, granule cells to differentiate with inhibitory interneuron or Purkinje cell properties in the cerebellum, and RGCs to differentiate with amacrine and horizontal cell properties in the retina [35–40]. Misexpression of Ptf1a in cortical pyramidal cells (row 7) is sufficient to induce features of an inhibitory peptidergic identity, including an alteration in cellular morphology and neurotransmitter status [19]. ‘+’ indicates an excitatory neurotransmitter status, ‘−’ indicates an inhibitory neurotransmitter status.

Mentions: Perhaps two of the most thoroughly investigated subtype-specifying transcription factors in the vertebrate nervous system, however, are Fezf2 and Ptf1a, and extensive research into their ability to direct aspects of neuronal identity and connectivity warrants a more comprehensive discussion of these examples. Like the examples described above, Fezf2 and Ptf1a are both necessary and sufficient for their respective neuronal subtypes, acting as a switch between developmentally related identities (figure 1). Knockout studies first demonstrated the necessity of Fezf2 for the specification of CFuPNs, particularly subcerebral projection neurons (SCPNs), in layer V of the cortex [9,10]. Without its expression, these neurons fail to acquire their typical layer V CFuPN identity, instead adopting a callosal projection neuron (CPN) or a layer VI corticothalamic projection neuron (CThPN) identity, as determined by changes to their molecular expression patterns, electrophysiological profile and axonal projections [10,32,41]. Furthermore, misexpression of Fezf2 in pyramidal cells of upper cortical layers alters their transcriptome to resemble CFuPNs, particularly SCPNs, inducing numerous downstream Fezf2-dependent markers and causing these cells to project axons to subcortical and subcerebral targets, as CFuPNs would [10,12,32]. Recently, Fezf2 has even been shown to be capable of redirecting neuronal identity in postmitotic cortical pyramidal cells of layer II/III and layer IV that have already acquired their layer specific identity, suggesting the power of Fezf2 to induce a CFuPN identity beyond a neuron's typical stage of developmental plasticity [11,33]. In these studies, misexpression of Fezf2 is sufficient to reprogramme the molecular expression, morphology, physiology and axonal targeting of these postmitotic neurons to resemble CFuPNs, while still maintaining them as viable, functional components of cortical circuitry.Figure 1.


From induction to conduction: how intrinsic transcriptional priming of extrinsic neuronal connectivity shapes neuronal identity.

Russ JB, Kaltschmidt JA - Open Biol (2014)

Fezf2 and Ptf1a are necessary and sufficient for a subtype-specific identity. Column 1 illustrates the role of Fezf2 in controlling CFuPN identity. In Fezf2−/− mice (row 1), CFuPNs primarily acquire a CPN identity, which causes these cells to project axons across the corpus callosum rather than to subcortical targets [10,32]. Misexpression of Fezf2 (+Fezf2) in CPNs or layer IV pyramidal cells in the cortex (rows 2 and 3), or in striatal medium spiny neurons (MSNs) (row 4), is sufficient to convert their identity to resemble that of CFuPNs, which includes changes in their molecular profile, neuronal morphology, and projection of axons to subcortical targets [11,12,33,34]. In the case of MSNs, this also includes a change in neurotransmitter status from inhibitory to excitatory [34]. Column 2 illustrates the role of Ptf1a in controlling an inhibitory neuronal identity in various regions of the CNS. Ptf1a is necessary for specifying the identity of dI4 interneurons in the spinal cord, inhibitory interneurons and Purkinje cells in the cerebellum, and amacrine and horizontal cells in the retina (rows 1–3). Without Ptf1a expression (Ptf1a−/−), these neurons adopt the features of their excitatory counterparts: dI5 cells in the spinal cord, granule cells in the cerebellum and retinal ganglion cells (RGCs) in the retina [13–17]. Misexpression of Ptf1a (+Ptf1a) in the developing spinal cord (row 4), cerebellum (row 5) or retina (row 6) is sufficient to promote an inhibitory interneuronal identity, causing dI5 cells to differentiate with dI4 properties in the spinal cord, granule cells to differentiate with inhibitory interneuron or Purkinje cell properties in the cerebellum, and RGCs to differentiate with amacrine and horizontal cell properties in the retina [35–40]. Misexpression of Ptf1a in cortical pyramidal cells (row 7) is sufficient to induce features of an inhibitory peptidergic identity, including an alteration in cellular morphology and neurotransmitter status [19]. ‘+’ indicates an excitatory neurotransmitter status, ‘−’ indicates an inhibitory neurotransmitter status.
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Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4221895&req=5

RSOB140144F1: Fezf2 and Ptf1a are necessary and sufficient for a subtype-specific identity. Column 1 illustrates the role of Fezf2 in controlling CFuPN identity. In Fezf2−/− mice (row 1), CFuPNs primarily acquire a CPN identity, which causes these cells to project axons across the corpus callosum rather than to subcortical targets [10,32]. Misexpression of Fezf2 (+Fezf2) in CPNs or layer IV pyramidal cells in the cortex (rows 2 and 3), or in striatal medium spiny neurons (MSNs) (row 4), is sufficient to convert their identity to resemble that of CFuPNs, which includes changes in their molecular profile, neuronal morphology, and projection of axons to subcortical targets [11,12,33,34]. In the case of MSNs, this also includes a change in neurotransmitter status from inhibitory to excitatory [34]. Column 2 illustrates the role of Ptf1a in controlling an inhibitory neuronal identity in various regions of the CNS. Ptf1a is necessary for specifying the identity of dI4 interneurons in the spinal cord, inhibitory interneurons and Purkinje cells in the cerebellum, and amacrine and horizontal cells in the retina (rows 1–3). Without Ptf1a expression (Ptf1a−/−), these neurons adopt the features of their excitatory counterparts: dI5 cells in the spinal cord, granule cells in the cerebellum and retinal ganglion cells (RGCs) in the retina [13–17]. Misexpression of Ptf1a (+Ptf1a) in the developing spinal cord (row 4), cerebellum (row 5) or retina (row 6) is sufficient to promote an inhibitory interneuronal identity, causing dI5 cells to differentiate with dI4 properties in the spinal cord, granule cells to differentiate with inhibitory interneuron or Purkinje cell properties in the cerebellum, and RGCs to differentiate with amacrine and horizontal cell properties in the retina [35–40]. Misexpression of Ptf1a in cortical pyramidal cells (row 7) is sufficient to induce features of an inhibitory peptidergic identity, including an alteration in cellular morphology and neurotransmitter status [19]. ‘+’ indicates an excitatory neurotransmitter status, ‘−’ indicates an inhibitory neurotransmitter status.
Mentions: Perhaps two of the most thoroughly investigated subtype-specifying transcription factors in the vertebrate nervous system, however, are Fezf2 and Ptf1a, and extensive research into their ability to direct aspects of neuronal identity and connectivity warrants a more comprehensive discussion of these examples. Like the examples described above, Fezf2 and Ptf1a are both necessary and sufficient for their respective neuronal subtypes, acting as a switch between developmentally related identities (figure 1). Knockout studies first demonstrated the necessity of Fezf2 for the specification of CFuPNs, particularly subcerebral projection neurons (SCPNs), in layer V of the cortex [9,10]. Without its expression, these neurons fail to acquire their typical layer V CFuPN identity, instead adopting a callosal projection neuron (CPN) or a layer VI corticothalamic projection neuron (CThPN) identity, as determined by changes to their molecular expression patterns, electrophysiological profile and axonal projections [10,32,41]. Furthermore, misexpression of Fezf2 in pyramidal cells of upper cortical layers alters their transcriptome to resemble CFuPNs, particularly SCPNs, inducing numerous downstream Fezf2-dependent markers and causing these cells to project axons to subcortical and subcerebral targets, as CFuPNs would [10,12,32]. Recently, Fezf2 has even been shown to be capable of redirecting neuronal identity in postmitotic cortical pyramidal cells of layer II/III and layer IV that have already acquired their layer specific identity, suggesting the power of Fezf2 to induce a CFuPN identity beyond a neuron's typical stage of developmental plasticity [11,33]. In these studies, misexpression of Fezf2 is sufficient to reprogramme the molecular expression, morphology, physiology and axonal targeting of these postmitotic neurons to resemble CFuPNs, while still maintaining them as viable, functional components of cortical circuitry.Figure 1.

Bottom Line: As the neuron's early connectivity is established, extrinsic signals from its pre- and postsynaptic partners feedback on the neuron to further refine its unique characteristics.As a result, disruption of one component of the circuitry during development can have vital consequences for the proper identity specification of its synaptic partners.Recent studies have begun to harness the power of various transcription factors that control neuronal cell fate, including those that specify a neuron's subtype-specific identity, seeking insight for future therapeutic strategies that aim to reconstitute damaged circuitry through neuronal reprogramming.

View Article: PubMed Central - PubMed

Affiliation: Weill Cornell/Rockefeller University/Sloan Kettering Tri-Institutional MD-PhD Program, New York, NY 10065, USA Neuroscience Program, Weill Cornell Medical College, New York, NY 10065, USA Developmental Biology Program, Sloan Kettering Institute, New York, NY 10065, USA.

ABSTRACT
Every behaviour of an organism relies on an intricate and vastly diverse network of neurons whose identity and connectivity must be specified with extreme precision during development. Intrinsically, specification of neuronal identity depends heavily on the expression of powerful transcription factors that direct numerous features of neuronal identity, including especially properties of neuronal connectivity, such as dendritic morphology, axonal targeting or synaptic specificity, ultimately priming the neuron for incorporation into emerging circuitry. As the neuron's early connectivity is established, extrinsic signals from its pre- and postsynaptic partners feedback on the neuron to further refine its unique characteristics. As a result, disruption of one component of the circuitry during development can have vital consequences for the proper identity specification of its synaptic partners. Recent studies have begun to harness the power of various transcription factors that control neuronal cell fate, including those that specify a neuron's subtype-specific identity, seeking insight for future therapeutic strategies that aim to reconstitute damaged circuitry through neuronal reprogramming.

Show MeSH
Related in: MedlinePlus