We have used the cloning of cancer-associated chromosomal aberrations as a means of discovering genes that play roles in growth and development. In the past, this strategy led to our discovery of six genes. We characterized the genomic and cDNA structures of each of these six genes and then turned to the functional characterization of a subset of the six. We have successfully generated homozygous """"""""null"""""""" animals for the neuronal lineage specific bHLH transcription factors NHLH1 and NHLH2 and for the immediate early response gene SIL, activated at the G0-G1 transition, and implicated in the etiology of T cell ALL when juxtaposed to another bHLH transcription factor discovered in this laboratory (the hematopoietic lineage determiner, SCL). The phenotype of the NHLH2 knockout animal is hypogonadal, obese, and sex drive deficient. Both males and females show a disruption of the normal hypothalamic-pituitary axis that controls sexual development at puberty. The female defect appears capable of being bypassed by the presence of normal male pheromones. The SIL knockout animals die between embryonic day 8.5-10.5. The affected fetuses show loss of normal regulation of left-right asymmetry of body axis, turning, and cardiac development. There is a correlating block in midline sonic hedgehog (Shh) signalling. The NHLH1 knockout mouse is capable of full embryonic maturation and birth but manifests an adult-onset locomotor defect and, in a subpopulation, premature death. The NHLH1 deficient animal suffers from stress-mediated sudden cardiac death. NHLH1/2 double knockout mice die within the early neonatal period. We have thus generated four model systems for studying the effect of two bHLH and one immediate early gene on embryonic development, cellular proliferation, and lineage determination. Through these systems we are elucidating factors that govern these critical aspects of growth and development.
| Erez, Ayelet; Perelman, Marina; Hewitt, Stephen M et al. (2004) Sil overexpression in lung cancer characterizes tumors with increased mitotic activity. Oncogene 23:5371-7 |
| Izraeli, S; Lowe, L A; Bertness, V L et al. (1999) The SIL gene is required for mouse embryonic axial development and left-right specification. Nature 399:691-4 |
