Biology subjects

Hammarlund, E.

Publications and source records attributed to Hammarlund, E..

5 recordsLinked to original sources

bioRxiv2026

FMR1 reduction alters cellular and circuit properties in human cortex

Transcriptional silencing of FMR1 results in Fragile X syndrome (FXS), the leading inherited cause of intellectual disability (ID) and autism. The Fmr1-/y mouse model has been used to identify FXS disease mechanisms, whereas mechanistic insights from human brain are lacking. By leveraging organotypic human cortical slices and viral tools to reduce FMR1 expression, we create a new model that captures cell type-specific transcriptomic changes similar to FXS patient cortex that are not seen in the Fmr1-/y mouse. Among these are ion channel subunit changes in deep layer pyramidal neurons, which are consistent with a robust hyperexcitability seen by whole-cell patch-clamp recordings, and increased synchronized activity revealed by 2-photon calcium imaging. Together, this work defines the impact of FMR1 reduction in human cortex and provides a new model for testing therapeutic interventions in FXS.

neuroscience↗

bioRxiv2025

Competing Programs Shape Cortical Sensorimotor-Association Axis Development

The neocortex is organized along a dominant sensorimotor-to-association (S-A) axis, anchored by modality-specific primary sensorimotor areas at one end and transmodal association areas that form distributed networks supporting abstract cognition at the other. The developmental mechanisms shaping this axis remain elusive. Here, we present converging multispecies evidence supporting the Multinodal Induction-Exclusion in Network Development (MIND) model, in which S-A patterning is governed by competing processes of induction and exclusion, driven by opposing transcriptomically-defined identity programs emerging from different nodes. Key molecular and connectional features of association cortices arise through pericentral programs, originating around fronto-temporal poles and partially regulated by retinoic acid. They progress inward toward central territories of the naive neocortex along fronto-temporally polarized trajectories. Central programs are induced through interactions between topographically separated first-order sensorimotor thalamocortical inputs and the neocortex, promoting the formation of primary areas while excluding pericentral programs. Influenced by SATB2 and ZBTB18, these evolutionarily conserved programs compete for the same territory and create spatial compartmentalization of axon guidance, cell-cell adhesion, retinoic acid signaling, synaptogenesis, Wnt signaling, and autism risk genes. Notably, PLXNC1 and SEMA7A exhibit anti-correlated expression and repulsive functions in shaping cortico-cortical connectivity along the S-A axis. These processes of induction and exclusion establish an S-A equilibrium and topography in which primary sensorimotor areas emerge as focal islands within the broader ocean of distributed associative networks. The MIND model provides a unifying framework for understanding experimental, evolutionary, and clinical phenomena, revealing induction and exclusion as antagonistic complementary principles shaping the S-A axis and processing hierarchies.

neuroscience↗

bioRxiv2024

Accelerated enzyme engineering by machine-learning guided cell-free expression

Enzyme engineering is limited by the challenge of rapidly generating and using large datasets of sequence-function relationships for predictive design. To address this challenge, we developed a machine learning (ML)-guided platform that integrates cell-free DNA assembly, cell-free gene expression, and functional assays to rapidly map fitness landscapes across protein sequence space and optimize enzymes for multiple, distinct chemical reactions. We applied this platform to engineer amide synthetases by evaluating substrate preference for 1,217 enzyme variants in 10,953 unique reactions. We used these data to build augmented ridge regression ML models for predicting amide synthetase variants capable of making 9 small molecule pharmaceuticals. Our ML-guided, cell-free framework promises to accelerate enzyme engineering by enabling iterative exploration of protein sequence space to build specialized biocatalysts in parallel.

synthetic biology↗

bioRxiv2023

MOXD1 is a gate-keeper of organ homeostasis and functions as a tumor-suppressor in neuroblastoma

Neuroblastoma is a childhood cancer believed to result from dysfunctional development. Its origin during embryogenesis remains poorly understood. The lack of appropriate models has hindered in-depth mapping of tumor-driving events. Here, we identify a novel tumor-suppressor gene that predicts poor survival in high-risk disease, by applying bulk and single cell RNA sequencing data of neuroblastoma and human fetal adrenal glands. Trunk neural crest-specific MOXD1 discriminates cell populations during normal and tumor development, with implications for deciphering neuroblastoma cell origin. We created an embryonic conditional knockout model and show that cell type-specific loss of MOXD1 leads to disrupted organ homeostasis and failed adrenal gland formation, home for neuroblastoma. We show that MOXD1 is a tumor suppressor gene in zebrafish, chick, and mice in vivo models. One-Sentence SummaryNeural crest-specific MOXD1 is a de novo tumor-suppressor gene in childhood cancers arising during embryogenesis.

cancer biology↗

bioRxiv2020

Cancer-associated HIF-2α impacts trunk neural crest stemness

The neural crest is a stem cell population that gives rise to sympathetic ganglia, the cell type of origin of neuroblastoma. Hypoxia Inducible Factor (HIF)-2 is associated with high risk neuroblastoma, however, little is known about its role in normal neural crest development. To address this important question, here we show that HIF-2 is expressed in trunk neural crest cells of human, murine and avian embryos. Modulating HIF-2 in vivo not only causes developmental delays but also induces proliferation and stemness of neural crest cells while altering the number of cells migrating ventrally to sympathoadrenal sites. Transcriptome changes after loss of HIF-2 reflect the in vivo phenotype. The results suggest that expression levels of HIF-2 must be strictly controlled and abnormal levels increase stemness and may promote metastasis. Our findings help elucidate the role of HIF-2 during normal development with implications also in tumor initiation at the onset of neuroblastoma.

developmental biology↗