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Analysis of the prenatal canine brain identifies species-specific and lineage-associated gene programs

ABSTRACT: Dogs have undergone intense selection for behavioral and morphological traits, but the prenatal programs that build the canine brain remain poorly defined. Here, we combine gross anatomy, micro-computed tomography, immunohistochemistry, region-resolved bulk RNA sequencing and comparative developmental alignment to characterize the canine forebrain at approximately embryonic days E40, E50 and E60. Across late gestation, the brain expanded rapidly, cortical folding emerged and major forebrain structures became progressively organized. RNA sequencing of frontal cortex, parietal cortex and medial ganglionic eminence identified distinct regional identities and broad maturation-associated changes. Shared programs emphasized synaptic and neuronal maturation, whereas region-restricted changes included cortical synapse-related and ganglionic-eminence cilium-related terms. Projection onto a human prenatal transcriptional trajectory placed the canine late-gestation samples within an approximate human mid-gestational window. SOX2-, PAX6-, TBR2/EOMES- and HOPX-positive progenitor populations remained detectable near term, demonstrating that cortical progenitor programs persist late into canine gestation while neuronal and glial maturation proceeds. Time-matched dog-human comparisons recovered conserved regulation together with oppositely regulated gene sets enriched for canine cholinergic or membrane-signaling functions and human receptor-tyrosine-kinase and ephrin signaling. Finally, disease- and canine-lineage-associated gene sets showed age- and region-structured expression. These data establish a prenatal canine brain framework for comparative neurodevelopment and provide a developmental context for interpreting disease- and lineage-associated genetic variation.

ORGANISM(S): Canis lupus familiaris

PROVIDER: GSE347336 | GEO | 2026/09/17

REPOSITORIES: GEO

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Project description:Malformations of cortical development are the underlying eitiology of many cases of Mental Retardation and Epilepsy. Subtle, below the resolution of current MRI, cortical dysplasias are probably involved in many cases of MR, Epilepsy and Autism for which no diagnosis can currently be made. Therefore, understanding the process of cortical development will be vital in diagnosing and eventual treatment of many patients with these conditions. More specifically, the cortex forms from two major populations of neuroblasts which reach their final destination in the cortex by differerent mechanisms. One is radial migration from ventricular neuroblasts to the cortical plate. These cells are excititory projection neurons and glia. The second pathway is from the ventral ganglionic eminences and tangential migration of the interneuronal population of primarily inhibitory neurons. Much less is known about the control of the latter process, and many of these currently undiagnosed subtle malformations may stem from abnormalities of this tangential migration. This project focuses on the understanding the control of the tangentially migrating inhibitory interneurons. We aim to uncover the transcriptional differences between two distinct neuronal populations, GFP positive cells in the ganglionic emience and GFP positive cells within the cortical plate, in order to understand the genetic control of tangential migration. We will acomplish this aim by targeting two different labeled transcripts againts the affymetrix mouse genome arrays. We hypothesis that there will be distinct differences in mRNA transcription profiles between the ganglionic eminence and cortical plate within developing interneurons. The differences in transcript profiles will be genes that regulate the migration and differentiation of these developing neurons. Transgenic mice have been generated which express green flourscent protien (GFP) based on the activity of the Dlx 5-6 promotor. Dlx 5-6 are highly regulated genes, and are expressed only in developing interneurons with in the embryonic brain. The expression of this gene begins at around E8 within the medial and lateral ganglionic eminence (GE) and then remain present as cells born within these regions migrate out into the developing cortex. Therefore, we can take advantage of these mice by harvesting embryos at a midpoint in their development (E13.5-14.5) and dissect out GFP positive cells from the ganglionic eminence and from the cortical plate. In order to obtain enough cells to extract sufficent mRNA, we have choosen to perform microdisction of the entire GE and entire cortical plate then break up the tissue into single cell suspension and Florescent activated cell sort (FACs) the populations of GFP + and GFP - cells. We then will extract the total RNA from the GFP postive cell populations using a Trizol based method and purify the RNA with a Quiagen column purification method. The purified RNA will then be amplified using the Affymetrix 1 or 2 round T7 based amplification procedure in order to generate the microgram quantities of labelled cRNA. The labelled biotin cRNA will be sent to the microarray consortium for hybridization againt the Affy mouse genome chip. Three embryos will be pooled in order to obtain sufficent RNA and 6 GFP positive GE and cortical plate samples will be used. The six replicates will be obtained from at least 3 different pregnant mice.

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Analysis of the prenatal canine brain identifies species-specific and lineage-associated gene programs

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