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Pregnancy Timeline by SemestersLungs begin to produce surfactantImmune system beginningHead may position into pelvisFull TermPeriod of rapid brain growthWhite fat begins to be madeHead may position into pelvisWhite fat begins to be madeImmune system beginningBrain convolutions beginBrain convolutions beginFetal liver is producing blood cellsSensory brain waves begin to activateSensory brain waves begin to activateInner Ear Bones HardenBone marrow starts making blood cellsBone marrow starts making blood cellsBrown fat surrounds lymphatic systemFetal sexual organs visibleFinger and toe prints appearFinger and toe prints appearHeartbeat can be detectedHeartbeat can be detectedBasic Brain Structure in PlaceThe Appearance of SomitesFirst Detectable Brain WavesA Four Chambered HeartBeginning Cerebral HemispheresFemale Reproductive SystemEnd of Embryonic PeriodEnd of Embryonic PeriodFirst Thin Layer of Skin AppearsThird TrimesterSecond TrimesterFirst TrimesterFertilizationDevelopmental Timeline
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Home | Pregnancy Timeline | News Alerts |News Archive Apr 6, 2015

Illustration of the development of the enteric nervous system and Hirschsprung disease:
advances in genetic and stem cell studies
. Nat Rev Neurosci. 2007 Jun;8(6):466-79.
Image credit: The University of Chicago Medicine




New clues on origin of Hirschsprung's disease

Rare disorder can spring from common mutations in nerve development.

Genetic studies in humans, zebrafish and mice have revealed how two different types of genetic variations team up to cause a rare condition called Hirschsprung's disease. The findings add to an increasingly clear picture of how flaws in early nerve development lead to poor colon function, which must often be surgically corrected. The study also provides a window into normal nerve development and the genes that direct it.

The results appear in the April 2 issue of the American Journal of Human Genetics.

About one in every 5,000 babies is born with Hirschsprung's disease, which causes bowel obstruction and can be fatal if not treated.

The disease arises early in development when nerves that should control the colon fail to grow. These nerves are part of the enteric (a mesh-like system of neurons that governs the function of the gastrointestinal system) nervous system, separate from the central nervous system.

The genetic causes of Hirschsprung's disease are complex, making it an interesting case study for researchers like Aravinda Chakravarti, Ph.D., a professor in the Johns Hopkins University School of Medicine's McKusick-Nathans Institute of Genetic Medicine. His research group began studying the condition in 1990. By 2002, his group performed the first-ever genomewide association study to identify common variants linked to the disease.

But while Chakravarti's and other groups have identified several gene variants associated with Hirschsprung's, these variants do not explain most cases of the disease. So Chakravarti and his colleagues conducted a genomewide study of genetic markers of more than 650 people with Hirschsprung's disease as compared with their parents and a healthy, unaffected control group.

One of their findings was a variation in a gene called Ret that had not been previously associated with Hirschsprung's, although some variations in Ret had previously been identified as somehow involved.

The other finding was of a variant located near genes known for making several semaphorins — proteins that guide developing nerve cells toward their final targets. Through studies in mice and zebrafish, researchers found that semaphorins are active in the developing enteric nervous system. They interact with Ret in a system of pathway signals.

"It looks like the semaphorin variant doesn't by itself lead to Hirschsprung's, but when there's a variant in Ret too, it causes the pathway to malfunction and can cause disease, We've found a new pathway that guides development of the enteric nervous system, one that nobody suspected had this role."

Aravinda Chakravarti PhD, professor, McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine.

No clinical genetic test yet exists for Hirschsprung's disease. So far, most of the genetic variants connected to Hirschsprung's are relatively common and are associated with less severe forms of the disease. So the hunt will continue for those rare gene variants of the more severe cases.

Innervation of the gut is segmentally lost in Hirschsprung disease (HSCR), a consequence of cell-autonomous and non-autonomous defects in enteric neuronal cell differentiation, proliferation, migration, or survival. Rare, high-penetrance coding variants and common, low-penetrance non-coding variants in 13 genes are known to underlie HSCR risk, with the most frequent variants in the ret proto-oncogene (RET). We used a genome-wide association (220 trios) and replication (429 trios) study to reveal a second non-coding variant distal to RET and a non-coding allele on chromosome 7 within the class 3 Semaphorin gene cluster. Analysis in Ret wild-type and Ret-null mice demonstrates specific expression of Sema3a, Sema3c, and Sema3d in the enteric nervous system (ENS). In zebrafish embryos, sema3 knockdowns show reduction of migratory ENS precursors with complete ablation under conjoint ret loss of function. Seven candidate receptors of Sema3 proteins are also expressed within the mouse ENS and their expression is also lost in the ENS of Ret-null embryos. Sequencing of SEMA3A, SEMA3C, and SEMA3D in 254 HSCR-affected subjects followed by in silico protein structure modeling and functional analyses identified five disease-associated alleles with loss-of-function defects in semaphorin dimerization and binding to their cognate neuropilin and plexin receptors. Thus, semaphorin 3C/3D signaling is an evolutionarily conserved regulator of ENS development whose dys-regulation is a cause of enteric aganglionosis.

Other authors on the paper are Qian Jiang, Stacey Arnold, Betty Doan, Ashish Kapoor, Albee Yun Ling, Maria X. Sosa, Moltu Guy, Krishna Praneeth Kilambi, Qingguang Jiang, Grzegorz Burzynski, Kristen West, Seneca Bessling, Jeffrey J. Gray and Andrew S. McCallion of The Johns Hopkins University; Tiffany Heanue and Vassilis Pachnis of the MRC National Institute for Medical Research; Paola Griseri and Isabella Ceccherini of the Istituto Gaslini; Jeanne Amiel and Stanislas Lyonnet of the French National Institute of Health and Medical Research and Paris Descartes University-Sorbonne Paris Cite; Raquel M. Fernandez and Salud Borrego of the University of Seville; Joke B.G.M. Verheij of the University of Groningen; and Robert M.W. Hofstra of the University of Rotterdam.

Affymetrix provided arrays used in the study described in this publication. Aravinda Chakravarti was a paid member of the Advisory Board of Affymetrix (2000-2013). This arrangement has been reviewed and approved by the Johns Hopkins University in accordance with its conflict of interest policies.

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