Investigating the mechanisms of reduced neuron generation in down syndrome

The National Institute of Child Health and Human Development awarded the University of Wisconsin - Madison $122,361 on January 31, 2026, under the Child Health and Human Development Extramural Research program (CFDA 93.865) to investigate the mechanisms of reduced neuron generation in Down syndrome.

The research evaluates how an extra copy of human chromosome 21 causes reduced cortical size and neuron formation during development. The work focuses on neural progenitor cell behavior during neurogenesis, specifically examining whether reduced progenitor populations result from prolonged cell cycle length, early differentiation into neurons, progenitor cell death, or a combination of mechanisms. The study analyzes human Down syndrome tissue and neural progenitors generated from trisomy 21 disorder-specific induced pluripotent stem cells, with particular attention to WNT signaling and mitochondrial dynamics pathways that regulate progenitor proliferation, apoptosis, and neuronal differentiation.

This is an F30 predoctoral fellowship supporting a graduate student researcher conducting the investigation. Performance occurs in Madison, Wisconsin, with a period of performance through October 31, 2028.

Abstract

Down syndrome (DS, trisomy 21, T21), the most common genetic cause of intellectual disability, is characterized by reduction in cortical size and neuron number. The fundamental question of how an extra copy of human chromosome 21 (HSA21) causes reduced brain growth and neuron formation remains unanswered. Extensive literature supports that fewer neurons are apparent at and before birth, suggesting impaired neurogenesis is a key cellular mechanism in DS. A highly controlled balance between neural progenitors and their differentiated, post-mitotic neuron counterparts is critical to generating the highly complex human neocortex, particularly the superficial cortex which is believed to contribute to human-specific higher order intelligence. Limited analysis of human DS tissue and neural progenitors generated from T21 disorder specific induced pluripotent stem cells (ipscs) support that fewer progenitors populate the developing DS cortex. However, IT remains unclear whether the reduction in progenitors is due to prolonged cell cycle, early differentiation into neurons, progenitor cell death, or a combination of some/all of these mechanisms. To date, an incomplete understanding of the seemingly basic, but important, neural progenitor cell (NPC) behavior during neurogenesis has prevented the unbiased, developmentally grounded, study of upstream sub- cellular and molecular signals that drive reduced neurogenesis in T21. My previously published work in the bhattacharyya lab shows global transcriptional changes in early npcs and specifically implicates WNT signaling and mitochondrial dynamics. Both of these pathways have broad developmental significance, particularly when IT comes to regulating progenitor proliferation, apoptosis and differentiation into neurons. The goals of this F30 pre-doctoral fellowship are to (1) evaluate the contribution of cell death, prolonged cell cycle length, and early differentiation to reduced progenitor pools in T21 and (2) leverage unbiased data in this critical period to define and test mechanistic pathways that cause reduced neurogenesis in T21. This F30 proposal will be the first study of produce a detailed assessment of T21 NPC cell cycle length and progression as well as exciting data regarding mitochondrial dynamics across this key transition from NPC to neuron in T21. The results from this project will meet the goals of the NIH include project by establishing scientific data critical to understanding early DS pathology and improving neurodevelopmental outcomes in individuals with down syndrome.