Brain-specific vulnerability to ubiquitous aspm loss in microcephaly

The National Institute of Neurological Disorders and Stroke awarded the University of Connecticut Health Center $462,950 on September 5, 2026, under the Extramural Research Programs in the Neurosciences and Neurological Disorders program (CFDA 93.853) to investigate the molecular mechanisms underlying brain-specific vulnerability to ASPM loss in microcephaly.

The research employs an ASPM knockout ferret model to define why mutations in the ubiquitously expressed ASPM gene cause severe brain-specific growth deficits while sparing other highly proliferative organs. The recipient will pursue two specific aims: Aim 1 quantifies proliferation and cell death across four ASPM-expressing tissues—cortex, lung, kidney, and intestine—in embryonic ferrets, and employs Seq-Scope spatial transcriptomics to map progenitor-specific stress responses in situ; Aim 2 identifies molecular mediators of this vulnerability through antibody-directed proximity labeling and related molecular techniques. The work is classified as a Project Grant (R21 mechanism), an exploratory research award.

Performance occurs in Farmington, Connecticut. The period of performance runs from the award date through August 31, 2028. The University of Connecticut Health Center, a state-controlled academic medical center and comprehensive research institution, serves as the prime recipient.

Abstract

Primary microcephaly presents a fundamental question in developmental biology: mutations in ubiquitously expressed genes cause severe, brain-specific growth deficits while sparing other highly proliferative organs. For example, aspm (abnormal spindle-like microcephaly-associated) encodes a centrosomal protein essential for cell proliferation throughout the body and is the most common cause of autosomal recessive microcephaly when mutated. Yet, loss of aspm results in profound reductions in brain size and intellectual disability without affecting body stature or the structure of tissues like the kidney or intestine. Despite its clinical importance, the molecular mechanisms conferring this "brain-specific vulnerability" remain unknown, largely because prior research has not directly compared the molecular consequences of aspm loss across affected and unaffected tissues. To bridge this GAP, we utilize a unique aspm knockout (KO) ferret model. While aspm KO mice exhibit mild phenotypes, our aspm KO ferrets faithfully recapitulate the severe human disease features-including a 25-40% reduction in cortical volume, premature progenitor delamination, and robust cell death-while maintaining normal body size. Our central hypothesis is that cortical progenitors possess an "intrinsic vulnerability" driven by cortex-specific aspm interactions that are absent in somatic tissues. To test the hypothesis, we propose two specific aims. Aim 1 will define the cellular and transcriptomic basis of this vulnerability: 1A) quantify proliferation and cell death across four aspm-expressing tissues (cortex, lung, kidney, and intestine) in embryonic ferrets; and 1B) employ SEQ-scope-a high-resolution spatial transcriptomics technology-to map progenitor-specific stress responses in situ. Aim 2 will identify the molecular mediators of this vulnerability: 2A) perform antibody- directed proximity labeling to define the in situ aspm interactome; and 2B) parallel centrosome affinity capture to profile centrosome composition across the same four tissues in WT and KO ferrets. Our research will elucidate why loss of the ubiquitous protein aspm causes brain-specific microcephaly, identifying novel therapeutic targets for neurodevelopmental disorders of cortical progenitors. Moreover, our methods and conceptual framework may advance the understanding of other neurological disorders where the loss of ubiquitously expressed genes causes tissue-restricted pathogenesis.