Regulation of cortical progenitors by Sufu and Shh signaling

Investigator: Samuel Pleasure, MD, PhD
Sponsor: NIH National Institute of Mental Health

Location(s): United States


The cerebral cortex is the seat of thought and will as well as the place where sensorimotor processing takes place. Both autism and schizophrenia are neuropsychiatric disorders associated with defects in cortical neuron development and function. This proposal studies the basic mechanisms governing the development of the cortex and explores how the cortex controls the successive production of cortical neurons followed by glia during development.

 In preliminary studies we found that mice lacking Sufu in the cortex after E10.5 have an almost complete failure to generate superficial cortical projection neurons but more intact production of deep layer cortical neurons. Preliminary analysis of these mutants demonstrates that progenitors for superficial neurons that appear during corticogenesis progressively lose their appropriate phenotype and instead take on the characteristics of ventral forebrain progenitors and oligodendrocyte precursors. Remarkably, deletion of Sufu at a slightly later age (E13.5) has essentially no effect on production of superficial neurons indicating a temporally sharp role for Sufu in controlling progenitor diversification and cell fate of neurons. Interestingly, when we examined mice with loss of Sufu at E13.5 there was a marked acceleration of the production of oligodendrocyte precursor cells at late embryonic and early postnatal stages in the cortex. These preliminary results have led us to propose a novel primary hypothesis, that controlled restriction of Shh signaling in the early cortical ventricular zone (between E10.5 and E13.5) is required for diversification of neocortical neurons and allows orderly progression from neurogenesis to oligogenesis. Further, our secondary hypothesis is that regulation of Shh signaling in the cortex also has profound effects on the production of oligodendrocyte precursors during cortical development. The aims below will test these hypotheses and examine the cellular and molecular mechanisms governing these phenotypes. 
Aim 1: Determine how Shh signaling blocks production of superficial cortical neurons. 
Aim 2: Identify roles of Shh signaling in controlling the postnatal neurogenesis and the production of oligodendrocyte precursors in the cortex. 
The studies proposed here will provide major new insights into two important questions - 
1) What is the role of Shh signaling in the developing forebrain and 
2) How is the orderly progression of production of deep layer neurons, then superficial layer neurons then glial cells controlled. 
This is of great importance to the fiel and also of major relevance to understanding the developmental underpinning of neuropsychiatric disease.