Ash1l loss-of-function results in structural birth defects and altered cortical development

Area of Science:

• Neuroscience
• Developmental Biology
• Genetics

Background:

• The histone methyltransferase ASH1L is critical for gene regulation during development.
• ASH1L variants are linked to autism spectrum disorder, but its role in brain development is unclear.
• Previous studies in mice showed Ash1l deficiency causes autistic-like behaviors.

Purpose of the Study:

• To investigate the impact of Ash1l loss-of-function on survival and craniofacial skeletal development.
• To analyze the role of Ash1l in cortical development and neuronal differentiation.
• To explore the molecular mechanisms underlying ASH1L's function in the brain.

Main Methods:

• Utilized a cre-inducible Ash1l knockout mouse model (Ash1l exon 4 deletion).
• Administered tamoxifen for early cortical development targeting (Emx1-Cre-ERT2; e10.5).
• Employed immunohistochemistry, EdU incorporation for birthdating, and single-cell RNA sequencing.

Main Results:

• Homozygous Ash1l knockout embryos showed no postnatal survival, despite normal embryonic proportions.
• Ash1l null mice exhibited shortened nasal bones and altered craniofacial development.
• Cortical-specific knockout led to increased SATB2+ neurons, ectopic deep layer neurons, and altered gene expression in upper layer neurons, indicating disrupted differentiation.

Conclusions:

• Ash1l is essential for postnatal survival and normal craniofacial development.
• ASH1L is indispensable for proper upper layer cortical neuron fate determination and gene expression.
• Findings provide insights into ASH1L's role in neurodevelopmental disorders, including autism.