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Catherine Dulac

Publications and source records attributed to Catherine Dulac.

18 recordsLinked to original sources
PubMed2025

The new frontier in understanding human and mammalian brain development.

Neurodevelopmental disorders that cause cognitive, behavioural or motor impairments affect around 15% of children and adolescents worldwide1, with diagnoses of profound autism and attention deficit hyperactivity disorder increasing in the USA and contributing to a major economic burden2,3. Yet the origins and mechanisms of these conditions remain poorly understood, limiting progress in therapies. Comprehensive cell atlases of the developing human brain, alongside those of model organisms such as mice and non-human primates, are now providing high-resolution measures of gene expression, cell-type abundance and spatial distribution. In this Perspective, we highlight recent studies that have identified novel developmental cell populations, revealed conserved and divergent patterns of cell genesis, migration and maturation across species, and begun testing hypotheses that link them to processes ranging from transcriptional control of cell fate specification to the emergence of complex behaviours. We present remaining conceptual and technical challenges and provide an outlook on how further studies of human and mammalian brain development can empower a deeper understanding of neurodevelopmental and neuropsychiatric disorders. Future efforts expanding to additional developmental stages, including adolescence, as well as whole-brain, multimodal and cross-species integration, will yield new insights into how development shapes the brain. These atlases promise to serve as essential references for unravelling mechanisms of brain function and disease vulnerability, and for advancing precision medicine.

Humans↗
PubMed2006

Labeled lines in the retinotectal system: markers for retinorecipient sublaminae and the retinal ganglion cell subsets that innervate them.

Axons of retinal ganglion cells (RGCs) carry visual information to the brain. In most vertebrates, the major synaptic target of RGCs is the optic tectum. In the chick, RGC axons form synapses in just 4 of 16 histologically recognizable laminae (the retinorecipient laminae [RRLs]), and arbors of individual RGCs are confined to a single RRL. To analyze the development and function of these parallel pathways, markers are required that selectively label them. Here, we have identified molecular markers for individual RRLs and for RGCs that project to them. Some of the markers may mediate or modulate signaling through the separate pathways: neuropeptides (substance P, neuromedin B, somatostatin-I and -II) and their receptors (substance P receptor), neurotransmitter synthetic enzymes (choline acetyltransferase) and the corresponding receptors (acetylcholine receptor beta2) and calcium-binding proteins (parvalbumin and calbindin). Other markers are adhesive proteins that could mediate selective connectivity of RGC subsets within specific RRLs (cadherin-7, cadherin-11, reelin and neuropilin-1). We further show that RGC subsets whose axons project to specific RRLs are heterogeneous with respect to the retinal sublaminae within which their dendrites arborize. Our results define laminar-specified circuits from retina to brain and support a model in which RGCs transmit information from multiple sources to single central laminae, where it can be integrated.

Animals↗
PubMed2006

Sparse encoding of natural scents.

Natural scents are mixtures of tens to hundreds of individual chemical compounds. While previous studies have investigated how the olfactory bulb responds to simple odorants, how the nose and the brain respond to and interpret complex mixtures is less clear. In a paper in this issue of Neuron, Lin et al. combined gas chromatography and intrinsic signal imaging to examine the responses of individual olfactory bulb glomeruli in the mouse to natural odors and their component parts.

Animals↗
PubMed2006

A multireceptor genetic approach uncovers an ordered integration of VNO sensory inputs in the accessory olfactory bulb.

Pheromone detection by the vomeronasal organ (VNO) is thought to rely on activation of specific receptors from the V1R and V2R gene families, but the central representation of pheromone receptor activation remains poorly understood. We generated transgenic mouse lines in which projections from multiple populations of VNO neurons, each expressing a distinct V1R, are differentially labeled with fluorescent proteins. This approach revealed that inputs from neurons expressing closely related V1Rs intermingle within shared, spatially conserved domains of the accessory olfactory bulb (AOB). Mitral cell-glomerular connectivity was examined by injecting intracellular dyes into AOB mitral cells and monitoring dendritic contacts with genetically labeled glomeruli. We show that individual mitral cells extend dendrites to glomeruli associated with different, but likely closely related, V1Rs. This organization differs from the labeled line of OR signaling in the main olfactory system and suggests that integration of information may already occur at the level of the AOB.

Animals↗
PubMed2006

MHC homologs in the nervous system--they haven't lost their groove.

Major histocompatibility complex (MHC) molecules have been implicated in a number of non-immune roles in the central nervous system, particularly in synaptic development and plasticity. The discovery of M10 (50% sequence identity to classical MHC molecules) proteins expressed in the vomeronasal organ adds to the list of non-traditional roles of MHC homologs. M10 molecules associate with the V2R class of vomeronasal receptors, a family of G-protein coupled receptors thought to function as pheromone receptors. Recent studies showing that classical MHC-binding peptides activate V2R-expressing neurons offer tempting clues that M10s might participate directly in the recognition of pheromone ligands, but M10 proteins do not bind to these peptides with significant affinity. Instead of presenting MHC-binding peptides, M10s might function as molecular chaperones to V2R receptors or more generally as modulators of neuronal function, as demonstrated elsewhere in the brain for classical MHC molecules.

Animals↗
PubMed2005

Olfactory inputs to hypothalamic neurons controlling reproduction and fertility.

In order to gain insight into sensory processing modulating reproductive behavioral and endocrine changes, we have aimed at identifying afferent pathways to neurons synthesizing luteinizing hormone-releasing hormone (LHRH, also known as gonadotropin-releasing hormone [GnRH]), a key neurohormone of reproduction. Injection of conditional pseudorabies virus into the brain of an LHRH::CRE mouse line led to the identification of neuronal networks connected to LHRH neurons. Remarkably, and in contrast to established notions on the nature of LHRH neuronal inputs, our data identify major olfactory projection pathways originating from a discrete population of olfactory sensory neurons but fail to document any synaptic connectivity with the vomeronasal system. Accordingly, chemosensory modulation of LHRH neuronal activity and mating behavior are dramatically impaired in absence of olfactory function, while they appear unaffected in mouse mutants lacking vomeronasal signaling. Further visualization of afferents to LHRH neurons across the brain offers a unique opportunity to uncover complex polysynaptic circuits modulating reproduction and fertility.

Animals↗
PubMed2005

Structure of a pheromone receptor-associated MHC molecule with an open and empty groove.

Neurons in the murine vomeronasal organ (VNO) express a family of class Ib major histocompatibility complex (MHC) proteins (M10s) that interact with the V2R class of VNO receptors. This interaction may play a direct role in the detection of pheromonal cues that initiate reproductive and territorial behaviors. The crystal structure of M10.5, an M10 family member, is similar to that of classical MHC molecules. However, the M10.5 counterpart of the MHC peptide-binding groove is open and unoccupied, revealing the first structure of an empty class I MHC molecule. Similar to empty MHC molecules, but unlike peptide-filled MHC proteins and non-peptide-binding MHC homologs, M10.5 is thermally unstable, suggesting that its groove is normally occupied. However, M10.5 does not bind endogenous peptides when expressed in mammalian cells or when offered a mixture of class I-binding peptides. The F pocket side of the M10.5 groove is open, suggesting that ligands larger than 8-10-mer class I-binding peptides could fit by extending out of the groove. Moreover, variable residues point up from the groove helices, rather than toward the groove as in classical MHC structures. These data suggest that M10s are unlikely to provide specific recognition of class I MHC-binding peptides, but are consistent with binding to other ligands, including proteins such as the V2Rs.

Animals↗
PubMed2005

Sex and the single splice.

Drosophila male courtship offers a unique experimental system to uncover the molecular and neural basis of genetically preprogrammed behavior. In this issue of Cell, Demir and Dickson (2005) and Stockinger et al. (2005) demonstrate that this behavior relies on a single splicing of the fruitless transcript, and on a specific olfactory-based neuronal circuit.

Alternative Splicing↗
PubMed2005

Molecular architecture of pheromone sensing in mammals.

Pheromones have evolved as a discrete class of secreted chemicals that signal the sex and social status of an individual and that promote coordinated motor programs and endocrine changes essential for breeding and aggression. The highly reproducible and species-specific character of the response to pheromones offers a unique experimental system to elucidate the coding of sexual and social information within the brain, and to provide new insights into the molecular and cellular basis of information processing leading to specific behaviours.

Animals↗
PubMed2004

Differential requirements for semaphorin 3F and Slit-1 in axonal targeting, fasciculation, and segregation of olfactory sensory neuron projections.

The formation of precise stereotypic connections in sensory systems is critical for defining accurate internal representations of the external world; however, the molecular mechanisms underlying the formation of sensory maps are poorly understood. Here, we examine the roles of two structurally unrelated repulsive guidance cues, semaphorin 3F (Sema3F) and Slit-1, in olfactory sensory axon fasciculation, targeting, and segregation. Using sema3F-/- mice, we show that Sema3F is critical for vomeronasal sensory neuron axonal fasciculation and for segregation of these sensory afferents from the main olfactory system; however, Sema3F plays only a minor role in targeting of apical vomeronasal neuron axons to the anterior accessory olfactory bulb (AOB). In addition, we show that Sema3F is required for lamina-specific targeting of olfactory sensory axons within the main olfactory system. In contrast to Sema3F, Slit-1 is dispensable for fasciculation of basal vomeronasal neuron axons but is critical for targeting these axons to the posterior AOB. These results reveal discrete and complementary roles for secreted semaphorins and slits in axonal targeting, fasciculation, and segregation of olfactory sensory neuron projections.

Animals↗
PubMed2003

Single-cell transcriptional analysis of neuronal progenitors.

The extraordinary cellular heterogeneity of the mammalian nervous system has largely hindered the molecular analysis of neuronal identity and diversity. In order to uncover mechanisms involved in neuronal differentiation and diversification, we have monitored the expression profiles of individual neurons and progenitor cells collected from dissociated tissue or captured from intact slices. We demonstrate that this technique provides a sensitive and reproducible representation of the single-cell transcriptome. In the olfactory system, hundreds of transcriptional differences were identified between olfactory progenitors and mature sensory neurons, enabling us to define the large variety of signaling pathways expressed by individual progenitors at a precise developmental stage. Finally, we show that regional differences in gene expression can be predicted from transcriptional analysis of single neuronal precursors isolated by laser capture from defined areas of the developing brain.

Animals↗
PubMed2003

Functional expression of murine V2R pheromone receptors involves selective association with the M10 and M1 families of MHC class Ib molecules.

The vomeronasal organ (VNO) of the mouse has two neuronal compartments expressing distinct families of pheromone receptors, the V1Rs and the V2Rs. We report here that two families of major histocompatibility complex (MHC) class Ib molecules, the M10 and the M1 families, show restricted expression in V2R-expressing neurons. Our data suggest that neurons expressing a given V2R specifically co-express one or a few members of the M10 family. Biochemical and immunocytochemical analysis demonstrates that in VNO sensory dendrites M10s belong to large multi-molecular complexes that include pheromone receptors and beta2-microglobulin (beta2m). In cultured cells, M10s appear to function as escort molecules in transport of V2Rs to the cell surface. Accordingly, beta2m-deficient mice exhibit mislocalization of V2Rs in the VNO and a specific defect in male-male aggressive behavior. The functional characterization of M10 highlights an unexpected role for MHC molecules in pheromone detection by mammalian VNO neurons.

Aggression↗
PubMed2002

Identification of a signaling network in lateral nucleus of amygdala important for inhibiting memory specifically related to learned fear.

We identified the Grp gene, encoding gastrin-releasing peptide, as being highly expressed both in the lateral nucleus of the amygdala, the nucleus where associations for Pavlovian learned fear are formed, and in the regions that convey fearful auditory information to the lateral nucleus. Moreover, we found that GRP receptor (GRPR) is expressed in GABAergic interneurons of the lateral nucleus. GRP excites these interneurons and increases their inhibition of principal neurons. GRPR-deficient mice showed decreased inhibition of principal neurons by the interneurons, enhanced long-term potentiation (LTP), and greater and more persistent long-term fear memory. By contrast, these mice performed normally in hippocampus-dependent Morris maze. These experiments provide genetic evidence that GRP and its neural circuitry operate as a negative feedback regulating fear and establish a causal relationship between Grpr gene expression, LTP, and amygdala-dependent memory for fear.

Amygdala↗
PubMed2002

Neuropilin-2 mediates axonal fasciculation, zonal segregation, but not axonal convergence, of primary accessory olfactory neurons.

The mechanisms that underlie axonal pathfinding of vomeronasal neurons from the vomeronasal organ (VNO) in the periphery to select glomeruli in the accessory olfactory bulb (AOB) are not well understood. Neuropilin-2, a receptor for secreted semaphorins, is expressed in V1R- and V3R-expressing, but not V2R-expressing, postnatal vomeronasal neurons. Analysis of the vomeronasal nerve in neuropilin-2 (npn-2) mutant mice reveals pathfinding defects at multiple choice points. Vomeronasal sensory axons are severely defasciculated and a subset innervates the main olfactory bulb (MOB). While most axons of V1R-expressing neurons reach the AOB and converge into distinct glomeruli in stereotypic locations, they are no longer restricted to their normal anterior AOB target zone. Thus, Npn-2 and candidate pheromone receptors play distinct and complementary roles in promoting the wiring and patterning of sensory neurons in the accessory olfactory system.

Animals↗
PubMed2002

Loss of sex discrimination and male-male aggression in mice deficient for TRP2.

The mouse vomeronasal organ (VNO) is thought to mediate social behaviors and neuroendocrine changes elicited by pheromonal cues. The molecular mechanisms underlying the sensory response to pheromones and the behavioral repertoire induced through the VNO are not fully characterized. Using the tools of mouse genetics and multielectrode recording, we demonstrate that the sensory activation of VNO neurons requires TRP2, a putative ion channel of the transient receptor potential family that is expressed exclusively in these neurons. Moreover, we show that male mice deficient in TRP2 expression fail to display male-male aggression, and they initiate sexual and courtship behaviors toward both males and females. Our study suggests that, in the mouse, sensory activation of the VNO is essential for sex discrimination of conspecifics and thus ensures gender-specific behavior.

Aggression↗
PubMed1991

A Monoclonal Antibody Defining a Carbohydrate Epitope Restricted to Glial Cells.

To follow cell lineage segregation of glial cell precursors in the central and peripheral nervous systems (CNS and PNS), we made monoclonal antibodies against purified avian myelin glycoproteins and made detailed studies of antibodies reacting with cellular antigens expressed early in development. We describe here the cellular and molecular characterization of the 4B3 epitope, which is first expressed at day 2.5 in quail embryos and appears strictly specific to glial cell membranes in the PNS and CNS. We demonstrate that, not only oligodendrocytes and astrocytes but also myelinating and non-myelinating Schwann cells, satellite cells of sensory and autonomic ganglia and enteric glial cells are 4B3-positive. This epitope was identified as an N-linked carbohydrate determinant shared by several unrelated molecules, one of them already described as the SMP glycoprotein.

Journal Article↗