Project description
Postnatal brain wiring in health and disease
The human brain continues to develop long after birth, with specialised inhibitory neurons migrating to their final destinations well into the first year of life. This prolonged migration, unique to humans, may represent a critical window of vulnerability for neurodevelopmental disorders such as autism and schizophrenia. However, studying this process has been hampered by the inaccessibility of human brain tissue and the lack of appropriate model systems. With the support of the Marie Skłodowska-Curie Actions programme, the NEURO-STREAM project leverages human stem cell-derived brain organoids to model postnatal inhibitory neuron migration. Researchers will use multi-omics and functional screening to identify the genetic networks driving this process and investigate how its disruption contributes to neurodevelopmental disease.
Objective
The development of cortical neural networks requires the migration and integration of ventrally-born inhibitory neurons (INs). Many diverse IN subtypes are regionally and temporally specified throughout development, but late-born INs derived from the CGE have recently received increased attention due to their expansion in humans and strong associations with neurodevelopmental disorder (NDD) pathogenesis. Recent studies have found that CGE INs form distinct migratory streams late in gestation and which persist postnatally. One such stream, the EC Stream, delivers INs to the entorhinal cortex up to 1 year after birth in humans, but was not found in macaques. This has implicated late IN migratory streams as a potential human-specific vulnerability in late and postnatal development. Despite this, the inaccessibility of tissue and lack of model systems has made genetic studies difficult.
The Knoblich Lab has recently modeled the emergence of late migratory streams in long-term cultures of CGE-patterned organoids derived from human iPSCs. We find that organoid streams undergo chain migration, recapitulating the molecular and cellular phenotypes of the in vivo postnatal EC Stream.
I propose to leverage this novel system to identify the transcriptional networks and genetic dependencies that postnatal migratory streams, while interrogating their potential role in neuropathogenesis. To do this, I will conduct multiomic single-cell characterization of early and late migratory IN populations to identify gene regulatory networks (GRNs) driving late migration. I will then conduct a multiplexed loss-of-function screen to identify stream-specific dependencies. Finally, I will leverage multiregional assembloid models of IN migration to interrogate the effects EC Stream perturbation in functional cortical maturation. Together, these objectives will uncover the transcriptomic drivers of the postnatal EC Stream and its previously unknown roles in neurodevelopment and disease.
Fields of science (EuroSciVoc)
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
This project's classification has been human-validated.
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
This project's classification has been human-validated.
Keywords
Project’s keywords as indicated by the project coordinator. Not to be confused with the EuroSciVoc taxonomy (Fields of science)
Project’s keywords as indicated by the project coordinator. Not to be confused with the EuroSciVoc taxonomy (Fields of science)
Programme(s)
Multi-annual funding programmes that define the EU’s priorities for research and innovation.
Multi-annual funding programmes that define the EU’s priorities for research and innovation.
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HORIZON.1.2 - Marie Skłodowska-Curie Actions (MSCA)
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Calls for proposals are divided into topics. A topic defines a specific subject or area for which applicants can submit proposals. The description of a topic comprises its specific scope and the expected impact of the funded project.
Funding Scheme
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Funding scheme (or “Type of Action”) inside a programme with common features. It specifies: the scope of what is funded; the reimbursement rate; specific evaluation criteria to qualify for funding; and the use of simplified forms of costs like lump sums.
HORIZON-TMA-MSCA-PF-EF - HORIZON TMA MSCA Postdoctoral Fellowships - European Fellowships
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Call for proposal
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(opens in new window) HORIZON-MSCA-2025-PF
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1030 Wien
Austria
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