Dr. Guillermo Lanuza
Jefe de Laboratorio
Genética del Desarrollo Neural Versión en español
Subject
The central nervous system is composed by a remarkable variety of neuronal and glial cell types that are assembled in functional circuits. The generation of neuronal and glial diversity results from an integrated series of developmental steps that control the differentiation of neural progenitors, the acquisition of specific identities, the extension of axonal processes and the establishment of synaptic connections. Our interest is to understand the basic mechanisms underlying the development of the nervous system, which will help to devise therapeutic strategies for diseases and damages of the nervous system.
Approach
We focus on the development of the hindbrain and the spinal cord, the posterior regions of the central nervous system, which harbor neural circuits that are essential for motor control and sensory processing. Our goal is to identify transcriptional regulators and signaling pathways whose functions organize to produce neuronal cell diversity. Our main experimental model is the mouse, and we use combined approaches of molecular genetics, microscopy and physiology.
Advances
1. Late neurogenesis in the developing mammalian spinal cord. The specification of Cerebrospinal Fluid-contacting Neurons in the Mouse Spinal Cord.
Considerable progress has been made in understanding the mechanisms that control the production of specialized neuronal types. However, how the timing of differentiation contributes to neuronal diversity in the neural tube is still a pending question.
We originally found the production of spinal cord neurons during advanced stages of embryonic development. Late neurogenesis in the spinal cord selectively give rise to an anatomically discrete cell type, called CerebroSpinal Fluid-contacting Neurons (CSF-cNs).
CSF-cNs maintain intimate contact with the fluid in the ventricles of the brain and the central canal of the spinal cord. Their strategic location and the conspicuous expression of mechanosensory and chemosensory ion channels suggest they are part of intriguing sensory systems intrinsic to the central nervous system. We discovered that CSF-cNs do not belong to previously known neuron populations and are born in a developmental period thought to exclusively generate glial cells, but not neurons.
To understand how CSF-cNs are born after the neurogenic-to-gliogenic switch, we focused on the mechanisms controlling their specification.
We identified that the delayed expression of the proneural protein Ascl1 in mouse spinal cord is key in CSF-cN differentiation. By performing in vivo cell fate mappings in the developing embryo, we found that CSF-cNs derive from progenitor cells that express Ascl1. The role of Ascl1 in late neurogenesis was assessed in several mouse mutant models. These experiments showed that the genetic abrogation of Ascl1 results in the absence of central canal neurons and the transformation of prospective CSF-cN progenitors into ependymal cells, the non-neuronal cells that covers the surface of the central canal. These results demonstrate that late spinal progenitors have the potential to produce neurons and that Ascl1 initiates CSF-cN differentiation, controlling the precise neuronal and non-neuronal composition of the spinal cord central canal.
2. Neuronal identity in ventral hindbrain and spinal cord.
The generation of distinct neuronal cell types at the right location is essential for building a functional nervous system.
In the developing neural tube, hindbrain serotonergic neurons and spinal glutamatergic V3 interneurons are produced from progenitors with a common transcriptional identity. However, serotonergic and V3 neurons have different properties and physiological functions, and they are confined to distinct anterior-posterior territories.
We found that the transcription factor Neurogenin3 (Neurog3) controls the correct specification of spinal cord neurons. Gain- and loss-of-function manipulations in the mouse and chick embryo showed that Neurog3 switches ventral progenitors from a serotonergic to V3 differentiation program. Neurog3 actively represses the expression of the serotoninergic determinant Ascl1 in spinal progenitors involving a Notch-dependent mechanism. In this way, Neurog3 establishes the posterior boundary of the serotonergic system by suppressing serotonergic specification in the spinal cord. These results explain how equivalent progenitors within the hindbrain and the spinal cord produce functionally distinct neuron cell types.
Reference: Carcagno, Di Bella, et al. Neurogenin3 restricts serotonergic neuron differentiation to the hindbrain. J.Neurosci (2014).
The central nervous system is composed by a remarkable variety of neuronal and glial cell types that are assembled in functional circuits. The generation of neuronal and glial diversity results from an integrated series of developmental steps that control the differentiation of neural progenitors, the acquisition of specific identities, the extension of axonal processes and the establishment of synaptic connections. Our interest is to understand the basic mechanisms underlying the development of the nervous system, which will help to devise therapeutic strategies for diseases and damages of the nervous system.
Approach
We focus on the development of the hindbrain and the spinal cord, the posterior regions of the central nervous system, which harbor neural circuits that are essential for motor control and sensory processing. Our goal is to identify transcriptional regulators and signaling pathways whose functions organize to produce neuronal cell diversity. Our main experimental model is the mouse, and we use combined approaches of molecular genetics, microscopy and physiology.
Advances
1. Late neurogenesis in the developing mammalian spinal cord. The specification of Cerebrospinal Fluid-contacting Neurons in the Mouse Spinal Cord.
Considerable progress has been made in understanding the mechanisms that control the production of specialized neuronal types. However, how the timing of differentiation contributes to neuronal diversity in the neural tube is still a pending question.
We originally found the production of spinal cord neurons during advanced stages of embryonic development. Late neurogenesis in the spinal cord selectively give rise to an anatomically discrete cell type, called CerebroSpinal Fluid-contacting Neurons (CSF-cNs).
CSF-cNs maintain intimate contact with the fluid in the ventricles of the brain and the central canal of the spinal cord. Their strategic location and the conspicuous expression of mechanosensory and chemosensory ion channels suggest they are part of intriguing sensory systems intrinsic to the central nervous system. We discovered that CSF-cNs do not belong to previously known neuron populations and are born in a developmental period thought to exclusively generate glial cells, but not neurons.
To understand how CSF-cNs are born after the neurogenic-to-gliogenic switch, we focused on the mechanisms controlling their specification.
We identified that the delayed expression of the proneural protein Ascl1 in mouse spinal cord is key in CSF-cN differentiation. By performing in vivo cell fate mappings in the developing embryo, we found that CSF-cNs derive from progenitor cells that express Ascl1. The role of Ascl1 in late neurogenesis was assessed in several mouse mutant models. These experiments showed that the genetic abrogation of Ascl1 results in the absence of central canal neurons and the transformation of prospective CSF-cN progenitors into ependymal cells, the non-neuronal cells that covers the surface of the central canal. These results demonstrate that late spinal progenitors have the potential to produce neurons and that Ascl1 initiates CSF-cN differentiation, controlling the precise neuronal and non-neuronal composition of the spinal cord central canal.
2. Neuronal identity in ventral hindbrain and spinal cord.
The generation of distinct neuronal cell types at the right location is essential for building a functional nervous system.
In the developing neural tube, hindbrain serotonergic neurons and spinal glutamatergic V3 interneurons are produced from progenitors with a common transcriptional identity. However, serotonergic and V3 neurons have different properties and physiological functions, and they are confined to distinct anterior-posterior territories.
We found that the transcription factor Neurogenin3 (Neurog3) controls the correct specification of spinal cord neurons. Gain- and loss-of-function manipulations in the mouse and chick embryo showed that Neurog3 switches ventral progenitors from a serotonergic to V3 differentiation program. Neurog3 actively represses the expression of the serotoninergic determinant Ascl1 in spinal progenitors involving a Notch-dependent mechanism. In this way, Neurog3 establishes the posterior boundary of the serotonergic system by suppressing serotonergic specification in the spinal cord. These results explain how equivalent progenitors within the hindbrain and the spinal cord produce functionally distinct neuron cell types.
Reference: Carcagno, Di Bella, et al. Neurogenin3 restricts serotonergic neuron differentiation to the hindbrain. J.Neurosci (2014).